This invention relates to novel condensed cyclic compounds having somatostatin receptor agonistic activity, a process for producing their compounds and a pharmaceutical composition characterized by containing them.
Somatostatin was first isolated from ovine hypothalamic tissues as a peptide (SST-14) consisting of 14 amino acids having inhibitory action on the secretion of growth hormone. At present, a somatostatin (SST-28) consisting of 28 amino acids has also been isolated. This somatostatin is a brain-gut peptide widely distributed not only in the hypothalamus but also in other organs such as cerebrum, limbic system, spinal cord, vagus nerve, autonomic nerve nodule, gastrointestinal mucosa and islets of Langerhans in the pancreas. It inhibits the secretion of pituitary/gastrointestinal hormones such as growth hormones, thyroid-stimulating hormones, gastrin, insulin and glucagon. It also inhibits the secretion of gastric acid, pancreatic exocrine secretion and movement/blood flow of the intestines.
As somatostatin receptors have so far been made known Types 1 to 5 (SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5). They have been recognized to show different expressions in each part of the central and peripheral regions [Life Sciences, Vol. 57, No. 13, p1249 (1995)].
At present, compounds analogous to the peptide-form somatostatins having specific hormone-inhibitory actions are under clinical development.
Condensed 4,1-benzoxazepine compounds having a substituent at the 3-position have been published in Chem. Pharm. Bull. 34 (1), p140-149 (1986), official gazettes of Japanese Published Unexamined Patent Application No. S57(1982)-35576, Japanese Published Unexamined Patent Application No. H6(1994)-239843(corresponding to EP-A-0567026), Japanese Published Unexamined Patent Application No. H7(1995)-179429(corresponding to EP-A-0645378), Japanese Published Unexamined Patent Application No. H7(1995)-179444(corresponding to EP-A-0645377), Japanese Published Unexamined Patent Application No. H7(1995)-267939, WO93/07129, WO96/09827, Japanese Published Unexamined Patent Application No. H8(1996)-259447, Japanese Published Unexamined Patent Application No. H8(1996)-157369.
2,3,4,5-Tetrahydro-2-oxo(or thioxo)-1H-1,4-condensed diazepine compounds having substituents at the 3- and 5-positions were published in J. Org. Chem., 38(20), 1973.
4,1-Benzoxazepine compounds having substituents at the 3- and 5-positions were published in Japanese Published Unexamined Patent Application No. H8(1996)-259447, WO96/09827.
The compounds now under development as somatostatin receptor agonists are peptide-form compounds. They have therefore many problems in various aspects such as duration of efficacy, dosing method, specificity and adverse drug reactions. In order to solve these problems, it is of great significance to originate and develop a non-peptide-form compound having an excellent somatostatin receptor agonistic action.
The present inventors have conducted extensive studies, in view of the above circumstances, to synthesize compounds represented by the following formula (I) or salts thereof for the first time. It is characterized by the chemical structure in which an amino group is bound via a divalent radical with the aromatic ring B in the formula (I): 
wherein ring A is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocyclic ring,
ring B is an optionally substituted aromatic hydrocarbon ring or an optionally substituted aromatic heterocyclic ring,
Z is an optionally substituted cyclic group or an optionally substituted linear hydrocarbon group,
R1 is a hydrogen atom, an optionally substituted hydrocarbon group or an optionally""substituted heterocyclic ring,
R2 is an optionally substituted amino group,
D is a bond or an optionally substituted divalent hydrocarbon group,
E is a bond, xe2x80x94CON(R1)xe2x80x94, xe2x80x94N(Ra)COxe2x80x94, xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94N(Rd)COOxe2x80x94, xe2x80x94N(Re)SO2xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94N(Rf)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94, xe2x80x94SO2xe2x80x94, 
(in which Ra, Rb, Rc, Rd, Re and Rf are respectively a hydrogen atom or an optionally substituted hydrocarbon group),
G is a bond or an optionally divalent substituted hydrocarbon group,
L is a divalent group,
ring B may form an optionally substituted non-aromatic condensed nitrogen-containing heterocyclic ring by combining with R2, and
X is two hydrogen atoms, an oxygen atom or a sulfur atom,
 is a single bond or a double bond, and
Y is a nitrogen atom when  is a double bond, or an oxygen atom, xe2x80x94N(R4)xe2x80x94 (in which R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O)n (in which n is 0, 1 or 2) when  is a single bond, or a salt thereof, and where the compounds have excellent properties as drugs with their specific chemical structures, such as, unexpectedly preferred somatostatin receptor agonistic action with low toxicity. The present invention has been completed based on these findings.
Namely, the present invention relates to
1) the above-mentioned compound (I) or a salt thereof,
2) a compound described in the above item 1, wherein Z is an optionally substituted cyclic group, G is an optionally divalent substituted hydrocarbon group and ring B does not form a non-aromatic condensed nitrogen-containing heterocyclic ring by combining with R2,
3) a compound described in the above item 2, wherein Y is a nitrogen atom when  is a double bond, or an oxygen atom or xe2x80x94N(R4)xe2x80x94 (in which R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) when  is a single bond,
4) a compound described in the above item 1, wherein  is a single bond,
5) a compound described in the above item 1, wherein ring B is an optionally substituted benzene ring,
6) a compound described in the above item 1, wherein ring B is an optionally substituted aromatic heterocyclic ring,
7) a compound described in the above item 1, wherein ring B is a benzene ring or a thiophene ring,
8) a compound described in the above item 1, wherein ring A is an optionally substituted benzene ring,
9) a compound described in the above item 1, wherein ring A is a benzene ring which may be substituted with halogen, hydroxy or C1-6 alkoxy,
10) a compound described in the above item 1, wherein R is an optionally substituted hydrocarbon group,
11) a compound described in the above item 1, wherein R1 is a C1-6 alkyl group or a C7-14 aralkyl group, which may be substituted with hydroxy, phenyl or amino which may be substituted with C1-6 alkyl-carbonyl or C1-6 alkylsulfonyl,
12) a compound described in the above item 1, wherein X i s an oxygen atom,
13) a compound described in the above item 1, wherein Y is an oxygen atom,
14) a compound described in the above item 1, wherein L is a hydrocarbon group which may be mediated by xe2x80x94Oxe2x80x94 or xe2x80x94Sxe2x80x94 and may be substituted,
15) a compound described in the above item 1, wherein L is a C1-6 alkylene group,
16) a compound described in the above item 1, wherein Z is an optionally substituted phenyl group,
17) a compound described in the above item 1, wherein Z is a phenyl group which is substituted with halogen,
18) a compound described in the above item 1, wherein D is an optionally substituted divalent hydrocarbon group.
19) a compound described in the above item 1, wherein D is a C1-6 alkylene group,
20) a compound described in the above item 1, wherein E is xe2x80x94CON(Ra)xe2x80x94 (in which Ra is a hydrogen atom or an optionally substituted hydrocarbon group),
21) a compound described in the above item 1, wherein E is xe2x80x94CONHxe2x80x94,
22) a compound described in the above item 1, wherein G is a C1-6 alkylene group,
23) a compound described in the above item 1, wherein R2 is an unsubstituted amino group,
24) a compound described in the above item 1, wherein ring B forms a tetrahydroisoquinoline ring by combining with R2,
25) a compound described in the above item 1, wherein ring A is an optionally substituted benzene ring, ring B is an optionally substituted benzene ring, Z is an optionally substituted phenyl group, D is a C1-6 alkylene group, G is a C1-6 alkylene group, R is an 2. optionally substituted hydrocarbon group, R is an unsubstituted amino group, E is xe2x80x94CONHxe2x80x94, L is a C1-6 alkylene group, X is an oxygen atom,
 is a single bond and Y is an oxygen atom,
26) a compound described in the above item 25, wherein ring A is a benzene ring which may be substituted with halogen, hydroxy or C1-6 alkoxy, ring B is a benzene ring, Z is a phenyl group which may be substituted with halogen and R1 is a C7-14 aralkyl group which may be substituted with hydroxy, phenyl or amino which may be substituted with C1-6 alkyl-carbonyl or C1-6 alkylsulfonyl,
27) a compound described in the above item 1, wherein ring A is an optionally substituted benzene ring, ring B is an optionally substituted aromatic heterocyclic ring, Z is an optionally substituted phenyl group, D is a C1-6 alkylene group, G is a C1-6 alkylene group, R1 is an optionally substituted hydrocarbon group, R2 is an unsubstituted amino group, E is xe2x80x94CONHxe2x80x94, L is a C1-6 alkylene group, X is an oxygen atom,  is a single bond and Y is an oxygen atom,
28) a compound described in the above item 27, wherein ring A is a benzene ring which may be substituted with halogen, hydroxy or C1-6 alkoxy, ring B is a thiophene ring, Z is a phenyl group which may be substituted with halogen and R1 is a C7-14 aralkyl group which may be substituted with hydroxy, phenyl or amino which may be substituted with C1-6 alkyl-carbonyl or C1-6 alkylsulfonyl,
29) a compound described in the above item 1, wherein ring A is a benzene ring which may be substituted with halogen, hydroxy, C1-6 alkoxy, halogeno-C1-6 alkoxy, C7-14 aralkyloxy, benzoyl-C1-6 alkoxy, hydroxy-C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy, C3-14 cycloalkyl-C1-6 alkoxy, imidazol-1-yl-C1-6 alkoxy, C7-14 aralkyloxy-carbonyl-C1-6 alkoxy or hydroxyphenyl-C1-6 alkoxy,
ring B is a benzene ring or a thiophene ring, which may be substituted with C1-6 alkoxy, or a tetrahydroisoquinoline ring by combining with R2,
Z is a C6-14 aryl group, a C3-10 cycloalkyl group, a piperidyl group, a thienyl group, a furyl group, a pyridyl group, a thiazolyl group, an-indolyl group or a C1-6 alkyl group, which may have 1 to 3 substituents selected from halogen, formyl, halogeno-C1-6 alkyl, C1-6 alkoxy and C1-6 alkoxy-carbonyl, oxo and pyrrolidinyl
D is a C1-6 alkylene group,
G is a bond or a C1-6 alkylene group which may have phenylene and which may be substituted with phenyl,
R1 is a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C6-14 aryl group or a C7-14 aralkyl group, which may be substituted with (1)halogen, (2)nitro, (3)amino which may have 1 to 2 substituents selected from C1-6 alkyl which may be substituted with C1-6 alkyl-carbonyl, benzyloxycarbonyl and C1-6 alkylsulfonyl, (4)hydroxy which may be substituted with (i)C1-6 alkyl which may be substituted with hydroxy, C1-6 alkyl-carbonyl, carboxy or C1-6 alkoxy-carbonyl, (ii)phenyl which may be substituted with hydroxy, (iii)benzoyl or (iv)mono- or di-C1-6 alkylamino-carbonyl, (5)C3-6 cycloalkyl, (6)phenyl which may be substituted with hydroxy or halogeno-C1-6 alkyl, or (7)thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl,
R2 is (1) an unsubstituted amino group, (2) a piperidyl group or (3) an amino group which have 1 to 2 substitutents selected from (i) benzyl, (ii) C1-6 alkyl which may be substituted with amino or phenyl, (iii) mono- or di-C1-6 alkylcarbamoyl, (iV) C1-6 alkoxy-carbonyl, (V) C1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (vii) C1-6 alkyl-carbonyl which may be substituted with halogen or amino,
E is a bond, xe2x80x94CON(Ra)xe2x80x94, xe2x80x94N(Ra)COxe2x80x94, xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94COOxe2x80x94, 
in which Ra, Rb and Rc is a hydrogen atom or a C1-6 alkyl group,
L is a C1-6 alkylene group which may be mediated by xe2x80x94Oxe2x80x94 and may be substituted with C1-6 alkyl,
X is an oxygen atom, and
 is a single bond or a double bond, and
Y is a nitrogen atom when  is a double bond, or an oxygen atom, xe2x80x94N(R4)xe2x80x94 (in which R is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O)n (in which n is 0, 1 or 2) when  is a single bond,
30) a compound described in the above item 1, which is
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
(3S,5S)-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-[2-(4-biphenyl)ethyl]-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(4-aminomethylphenyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(2-aminomethylthiophen-5-yl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-[3-[(1-amino-1-methyl)ethyl]phenyl]-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-(4-hydroxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-1-(4-acetylaminobenzyl)-5-(3-aminomethylphenyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-(4-methanesulfonylaminobenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-hydroxybenzyl)-7-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-[4-[(1-amino-1-methyl)ethyl]phenyl]-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-[2-(4-hydroxyphenyl)ethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, or
3,5-trans-N-(2-fluorobenzyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4,1-benzoxazepine-3-acetamide or a salt thereof,
31) a process for producing the compound of the formula: 
wherein the symbols are as defined in claim 1, or a salt thereof, which comprises reacting a compound of the formula: 
wherein the symbols are as defined in claim 1, or a salt thereof, with a compound of the formula: 
wherein the symbols are as defined in claim 1, or a salt thereof,
32) a pharmaceutical composition which comprises a compound (I) described in the above item 1 or a salt thereof in admixture with a pharmaceutically acceptable carrier or excipient,
33) a pharmaceutical composition described in the above item 32, which is a somatostatin receptor agonist,
34) a pharmaceutical composition described in the above item 32, which is for treating or preventing diabetes, obesity, diabetic complication or inveterate diarrhea,
35) use of a compound (I) described in the above item 1 or a salt thereof for manufacturing a pharmaceutical composition,
36) use of a compound (I) described in the above item 1 or a salt thereof for manufacturing a pharmaceutical composition which is a somatostatin receptor agonist,
37) use of a compound (I) described in the above item 1 or a salt thereof for manufacturing a pharmaceutical composition for treating or preventing diabetes, obesity, diabetic complication or inveterate diarrhea,
38) a method for activating somatostatin receptors in a mammal which comprises administering an effective amount of a compound (I) described in the above item 1 or a salt thereof to said mammal,
39) a method for using a compound (I) described in the above item 1 or a salt thereof as somatostatin receptor agonists in a mammal which comprises administering an effective amount of a compound of claim 1 or a salt thereof to said mammal, and
40) a method for treating or preventing diabetes, obesity, diabetic complication or inveterate diarrhea in a mammal which comprises administering an effective amount of a compound (I) described in the above item 1 or a salt thereof to said mammal.
In the formula mentioned above, ring A stands for an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic ring. As ring A is preferably used, for example, an optionally substituted aromatic hydrocarbon group is used. Especially an optionally substituted benzene ring is frequently used.
As said xe2x80x9caromatic hydrocarbon groupxe2x80x9d represented by ring A are mentioned aromatic hydrocarobons consisting of 6 to 14 carbon atoms (for example, C6-14 aryl such as benzene, naphthalene, anthracene and phenanthrene). Especially benzene is frequently used.
As said xe2x80x9caromatic heterocyclic ringxe2x80x9d represented by ring A are mentioned, for example, monocyclic aromatic heterocyclic ring and polycyclic aromatic condensed heterocyclic ring. As said xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d are mentioned 5- or 6-membered monocyclic aromatic heterocyclic rings having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. More specifically, furan, thiophene, pyrrole, oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine and triazine are used for example. As said xe2x80x9cpolycyclic aromatic condensed heterocyclic ringxe2x80x9d are mentioned, for example, bi- or tri-cyclic aromatic condensed heterocyclic ring which is formed by the condensation of the benzene ring and said xe2x80x9cmonocyclic aromatic heterocyclic ringsxe2x80x9d. More specifically, benzofuran, isobenzofuran, benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzoisoxazole, benzthiazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnolin, quinazoline, quinoxaline, phthalazine, naphthylidine, purine, pteridine, carbazole, xcex1-carbolin, xcex2-carbolin, xcex3-carbolin, acridine, phenoxazine, phenothiazine, phenazine, phenoxathine, thianthrene, phenatrizine, phenanthroline, indolidine, pyrrolo[1,2-b]pyridazine, pyrazolo[1,5-a)pyridine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo(1,2-a]pyridazine, imidazo[1,2-a]pyrimidine, 1,2,4-triazolo[4,3-a]pyridine and 1,2,4-triazolo[4,3-b]pyridazine are used for example. As said xe2x80x9caromatic heterocyclic ringxe2x80x9d represented by ring A is preferably used, for example, said xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d. Especially, furan, thiophene and pyridine are frequently used for example.
As the substituents that said xe2x80x9caromatic hydrocarbon groupxe2x80x9d, xe2x80x9caromatic heterocyclic ringxe2x80x9d and xe2x80x9cbenzene ringxe2x80x9d may have are mentioned, for example, halogen atom (for example, fluorine, chlorine, bromine and iodine), C1-6 alkyl (for example, methyl, ethyl, propyl, butyl, sec-butyl, t-butyl and isopropyl), halogeno-C1-6 alkyl (for example, C1-6 alkyl groups substituted with 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d such as trifluoromethyl), phenyl, benzyl, C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, t-butoxy and isopropoxy), halogeno-C1-6 alkoxy (for example, C1-6 alkoxy groups substituted with 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d such as trifluoromethoxy and chloropropyloxy), phenoxy, C7-14 aralkyloxy (for example, benzyloxy, phenethyloxy and phenylpropyloxy), formyloxy, C1-6 alkyl-carbonyloxy (for example, acetyloxy), C1-6 alkylthio (for example, methylthio, ethylthio, propylthio, butylthio, sec-butylthio, t-butylthio and isopropylthio), halogeno-C1-6 alkylthio (for example, C1-6 alkylthio groups substituted with 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d such as trifluoromethylthio), hydroxy, mercapto, cyano, nitro, carboxy, formyl, C1-6 alkyl-carbonyl (for example, acetyl and propionyl), benzoyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl and propoxycarbonyl), phenoxycarbonyl, amino, mono- or di-C1-6 alkylamino (for example, methylamino, ethylamino, dimethylamino and diethylamino), formylamino, C1-6 alkyl-carbonylamino (for example, acetylamino, propyonylamino and butyrylamino), carbamoyl, mono- or di-C1-6 alkyl-carbamoyl (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl), sulfo, C1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl and propylsulfonyl), benzoyl-C1-6 alkoxy (for example, hydroxyethyloxy), hydroxy-C1-6 alkoxy (for example, hydroxyethyloxy), C1-6 alkoxy-carbonyl-C1-6 alkoxy (for example, methoxycarbonylmethyloxy), C3-14 cycloalkyl-C1-6 alkoxy (for example, cyclohexylmethyloxy), imidazol-1-yl-C1-6 alkoxy (for example, imidazol-1-ylpropyloxy), C7-14 aralkyloxy-carbonyl-C1-6 alkoxy (for example, benzyloxycarbonylmethyloxy), hydroxyphenyl-C1-6 alkoxy (for example, [3-(4-hydroxyphenyl)propyl]oxy), C7-14 aralkyloxy-carbonyl (for example, benzyloxy-carbonyl), mono- or di-C1-6 alkylamino-C1-6 alkoxy (for example, methylaminomethoxy, ethylaminoethoxy, dimethylaminomethoxy) and mono- or di-C1-6 alkylamino-carbonyloxy (for example, methylaminocarbonyloxy, ethylaminocarbonyloxy, dimethylaminocarbonyloxy). Especially, said xe2x80x9chalogen atomxe2x80x9d is frequently used. Said xe2x80x9caromatic hydrocarbon ringxe2x80x9d, xe2x80x9caromatic heterocyclic ringxe2x80x9d and xe2x80x9cbenzene ringxe2x80x9d may have 1 to 4 substituents selected from their substituents.
A preferable example of ring A is an optionally substituted benzene ring and more preferably, a benzene ring which may be substituted with halogen, hydroxy, C1-6 alkoxy, halogeno-C1-6 alkoxy, C7-14 aralkyloxy, benzoyl-C1-6 alkoxy, hydroxy-C1-6 alkoxy, C1-6 alkoxy-carbonyl-C 1-6 alkoxy, C3-14 cycloalkyl-C1-6 alkoxy, imidazol-1-yl-C1-6 alkoxy, C7-14 aralkyloxy-carbonyl-C1-6 alkoxy or hydroxyphenyl-C1-6 alkoxy. The most preferable examples of ring A are a benzene ring which may be substituted with halogen(preferably, chlorine and etc.), hydroxy or C1-6 alkoxy(preferably, methoxy and etc.).
Preferable position of substituents for ring A is 7- or 8-position.
Preferable number of substituents for ring A is 1 or 2.
In the formula mentioned above, ring B stands for an optionally substituted aromatic hydrocarbon group or an optionally substituted aromatic heterocyclic ring. As ring B, an optionally substituted aromatic hydrocarbon group is preferably used for example. Especially an optionally substituted benzene ring is frequently used.
As said xe2x80x9caromatic hydrocarbon groupsxe2x80x9d represented by ring B are mentioned, for example, an aromatic hydrocarbon group consisting of 6 to 14 carbon atoms (C6-14 aryl groups of, for example, benzene, naphthalene, anthracene and phenanthrene). Especially benzene is frequently used.
As said xe2x80x9caromatic heterocyclic ringxe2x80x9d represented by ring B are mentioned, for example, monocyclic aromatic heterocyclic rings and polycyclic aromatic condensed heterocyclic rings. As said xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d are mentioned 5- or 6-membered monocyclic aromatic heterocyclic rings having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms. More specifically, furan, thiophene, pyrrole, oxazole, isooxazole, thiazole, isothiazole, imidazole, pyrazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, furazane, 1,2,3-thiadiazole, 1,2,4-thiadiazole, 1,3,4-thiadiazole, 1,2,3-triazole, 1,2,4-triazole, tetrazole, pyridine, pyridazine, pyrimidine and triazine are used for example. As said xe2x80x9cpolycyclic aromatic condensed heterocyclic ringxe2x80x9d are mentioned, for example, bi- or tricyclic aromatic condensed heterocyclic rings which are formed by the condensation of the benzene ring and said xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d. More specifically, benzofuran, isobenzofuran, benzo[b]thiophene, indole, isoindole, 1H-indazole, benzimidazole, benzoxazole, 1,2-benzisooxazole, benzothiazole, 1,2-benzisothiazole, 1H-benzotriazole, quinoline, isoquinoline, cinnolin, quinazoline, quinoxaline, phthalazine, naphthylidine, purine, pteridine, carbazole, xcex1-carbolin, xcex2-carbolin, xcex3-carbolin, acridine, phenoxazine, phenothiazine, phenazine, phenoxathine, thianthorene, phenatrizine, phenanthroline, indolidine, pyrrolo[1,2-b]pyridazine, pyrazolo[1,5-a]pyridine, imidazo[1,2-a]pyridine, imidazo[1,5-a]pyridine, imidazo[l,2-a]pyridazine, imidazo[1,2-a] pyrimidine, 1,2,4-triazolo[4,3-a]pyridine and 1,2,4-triazolo[4,3-b]pyridazine are used for example. As said xe2x80x9caromatic heterocyclic ringxe2x80x9d represented by ring B is preferably used, for example, xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d. Especially, furan, thiophene and pyridine(more especially, thiophene) are frequently used.
As the substituents that said xe2x80x9caromatic hydrocarbon ringxe2x80x9d, xe2x80x9caromatic heterocyclic ringxe2x80x9d and xe2x80x9cbenzene ringxe2x80x9d may have are mentioned, for example, the same substituents that said xe2x80x9caromatic hydrocarbonxe2x80x9d at ring A may have. Said xe2x80x9caromatic hydrocarbon ringxe2x80x9d, xe2x80x9caromatic heterocyclic ringxe2x80x9d and xe2x80x9cbenzene ringxe2x80x9d may have 1 to 4 substituents selected from these substituents.
Preferable example of ring B are an optionally substituted benzene ring or aromatic heterocyclic ring and more preferably, a benzene ring or a thiophene ring, which may be substituted with C1-6 alkoxy. The most preferable example of ring B is an unsubstituted benzene ring or an unsubstituted thiophene ring.
In the formula mentioned above, ring B may form an optionally substituted non-aromatic condensed nitrogen-containing heterocyclic ring by combining with R2.
Examples of non-aromatic condensed nitrogen-containing heterocyclic rings formed when ring B combines with R2 include bi-cyclic non-aromatic condensed nitrogen-containing heterocyclic ring which is formed by the condensation of benzene ring and the 5- or 6-membered monocyclic non-aromatic heterocyclic ring having 1 to 3 hetero atoms selected from nitrogen, oxygen and sulfur and preferably, tetrahydroisoquinoline (for example, 1,2,3,4-tetrahydroisoquinoline), tetrahydroquinoline (for example, 1,2,3,4-tetrahydroquinoline), isoindoline, indoline, 2,3-dihydrobenzthiazole, 2,3-dihydrobenzoxazole, 3,4-dihydro-2H-1,4-benzthiazine, 3,4-dihydro-2H-1,4-benzoxazine, 1,2,3,4-tetrahydroquinoxaline, 2,3,4,5-tetrahydro-1,4-benzoxazepine and more preferably, tetrahydroisoquinoline.
As the substituents that said xe2x80x9cnon-aromatic condensed nitrogen-containing heterocyclic ringxe2x80x9d may have are mentioned, for example, the same substituents that said xe2x80x9caromatic hydrocarbon ring, aromatic heterocyclic ring and benzene ringxe2x80x9d represented by ring B may have. The said xe2x80x9cnon-aromatic condensed nitrogen-containing heterocyclic ringxe2x80x9d may have 1 to 4 substituents selected from the above.
In the formula mentioned above, Z stands for an optionally substituted cyclic group or an optionally substituted linear hydrocarbon group. As said xe2x80x9ccyclic !D groupxe2x80x9d represented by Z are mentioned cyclic hydrocarbon group and heterocyclic group, for example. As ring Z is preferably used an optionally substituted aromatic hydrocarbon group and an optionally substituted aromatic heterocyclic group for example. Especially, an optionally substituted phenyl group is frequently used.
Said xe2x80x9ccyclic hydrocarbon groupxe2x80x9d is represented by alicyclic hydrocarbon group consisting of 3 to 14 carbon atoms or aromatic hydrocarbon group consisting of 6 to 14 carbon atoms. As said xe2x80x9calicyclic hydrocarbon groupxe2x80x9d are mentioned, for example, C3-14 cycloalkyl (for example, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl), C3-14 cycloalkenyl (for example, cyclopentenyl and cyclohexenyl), C5-14 cycloalkadienyl (for example, 2,4-cycloptentadienyl and 1,3-cyclohexadienyl) and indanyl. As said xe2x80x9caromatic hydrocarbon groupxe2x80x9d are mentioned C6-14 aryl (for example, phenyl, naphthyl, anthracenyl and phenanthrenyl) for example.
As said xe2x80x9cheterocyclic groupxe2x80x9d are mentioned, for example, monocyclic heterocyclic group and polycyclic condensed heterocyclic group. As said xe2x80x9cmonocyclic heterocyclic groupxe2x80x9d are mentioned 5- or 6-membered monocyclic heterocyclic group having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atoms, for example. More specifically, monocyclic aromatic heterocyclic group (for example, furyl, thienyl, pyrrolyl, oxazolyl, isooxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl and triazinyl), monocyclic non-aromatic heterocyclic group (for example, oxiranyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuryl, thiolanyl, piperidyl, tetrahydropyranyl, morpholinyl, thiomorpholinyl and piperazinyl) are used for example. As said xe2x80x9cpolycyclic condensed heterocyclic groupxe2x80x9d are mentioned, for example, bi- or tri-cyclic aromatic condensed heterocyclic group which is formed by the condensation of benzene ring and said xe2x80x9cmonocyclic aromatic heterocyclic ringxe2x80x9d or these partial reduction. More specifically, polycyclic aromatic condensed heterocyclic groups (for example, benzofuryl, isobenzofuryl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzothiazolyl, 1,2-benzoisothiazolyl, 1H-benzotriazolyl, quinolyl, isoquinolyl, cinnolyl, quinazolinyl, quinoxalinyl, phthalazinyl, naphthylidinyl, purinyl, pteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxathinyl, thianthorenyl, phenatrizinyl, phenanthrolinyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridazine, imidazo[1,2-a]pyrimidine, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]pyridazinyl) and polycyclic non-aromatic condensed heterocyclic groups (for example, isochromanyl, chromanyl, indolinyl, isoindolinyl, 1,2,3,4-tetrahydroisoquinolinyl and 1,2,3,4-tetrahydroquinolinyl) are used.
As the substituents that said xe2x80x9ccyclic groupxe2x80x9d represented by Z may have are mentioned, for example, the same substituents that said xe2x80x9caromatic hydrocarbon groupxe2x80x9d in ring A may have, oxo and thioxo. Said xe2x80x9ccyclic groupxe2x80x9d may have 1 to 5 substituents selected from these substituents.
As said xe2x80x9clinear hydrocarbon groupxe2x80x9d represented by Z are mentioned, for example, xe2x80x9caliphatic hydrocarbon groupxe2x80x9d of xe2x80x9chydrocarbon groupxe2x80x9d represented by R1. As the substituents that xe2x80x9clinear hydrocarbon groupxe2x80x9d represented by Z may have are mentioned, for example, the same substituents that said xe2x80x9caromatic hydrocarbon groupxe2x80x9d represented by R may have.
Preferable examples of Z is a C6-14 aryl group (preferably, phenyl), a C3-10 cycloalkyl group, a piperidyl group, a thienyl group, a furyl group, a pyridyl group, a thiazolyl group, an indolyl group or a C1-6 alkyl group, which may have 1 to 3 substituents selected from halogen, forymyl, halogeno-C1-6 alkyl, C1-6 alkoxy, C1-6 alkoxy-carbonyl, oxo and pyrrolidinyl, and more preferably, a phenyl group substituted with halogen (preferably, fluorine).
Preferable position of substituents for cyclic group represented by Z is ortho-position.
Preferable number of substituents for cyclic group represented by Z is one.
In the formula mentioned above, D stands for a bond or an optionally substituted divalent hydrocarbon group, preferably divalent hydrocarbon groups.
As said xe2x80x9cdivalent hydrocarbon groupxe2x80x9d represented by D is used a straight chain divalent hydrocarbon group with 1 to 10 carbons, for example. Specifically, C1-10 alkylene (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene, peptamethylene and octamethylene) is mentioned for example. More specifically, C1-6 alkylene (for example, methylene, ethylene, propylene, butylene, pentamethylene, hexamethylene) is mentioned. Said xe2x80x9cdivalent hydrocarbon groupxe2x80x9d may have a C3-6 cycloalkylene (for example, 1,4-cyclohexylene), phenylene (for example, 1,4-phenylene and 1,2-phenylene), for example, at any position.
As the substituents that said xe2x80x9cdivalent hydrocarbon groupxe2x80x9d represented by D may have are mentioned, for example, C1-6 alkyl (for example, methyl, ethyl, propyl and isopropyl), halogeno-C1-6 alkyl (for example, C1-6 alkyl substituted by said 1 to 5 xe2x80x9chalogen atomsxe2x80x9d such as trifluoromethyl), phenyl and benzyl. Said xe2x80x9cdivalent hydrocarbon groupxe2x80x9d may have 1 to 3 of these substituents.
As D, C1-6 alkylene (for example, methylene, ethylene and propylene, preferably methylene) is frequently used.
In the formula mentioned above, G stands for a bond or an optionally substituted divalent hydrocarbon group. As the xe2x80x9coptionally substituted divalent hydrocarbon groupxe2x80x9d represented by G is used the same as the above-mentioned xe2x80x9coptionally substituted divalent hydrocarbon groupxe2x80x9d represented by D for example.
Preferable examples of G are a bond or a C1-6 alkylene group which may have phenylene and which may be substituted with phenyl and C1-6 alkylene (for example, methylene, ethylene, propylene) is frequently used as G. C1-6 alkylene represented by G may be mediated by phenylene between G and E or Z, or may include phenylene in C1-6 alkylene.
In the formula mentioned above, R1 stands for hydrogen atom, an optionally substituted hydrocarbon group or an optionally substituted heterocyclic ring. As R1 is preferably used an optionally substituted hydrocarbon group.
As said xe2x80x9chydrocarbon groupxe2x80x9d represented by R1 are mentioned, for example, aliphatic hydrocarbon groups, alicyclic hydrocarbon groups, aryl groups and aralkyl groups. Especially, aliphatic hydrocarbon is frequently used.
As said xe2x80x9caliphatic hydrocarbon groupxe2x80x9d are mentioned aliphatic hydrocarbon groups having 1 to 10 carbon atoms (for example, C1-10 alkyl, C2-10 alkenyl and C2-10 alkynyl). As said xe2x80x9cC1-10 alkylxe2x80x9d, are mentioned, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, t-butyl, pentyl, isopentyl, neopentyl, 1-methylpropyl, hexyl, isohexyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 3,3-dimethylpropyl, 2-ethylbutyl and heptyl. Preferably, C3-5 alkyl (for example, propyl, isopropyl, isobutyl and neopentyl) is mentioned. Especially, isobutyl and neopentyl are frequently used. As said xe2x80x9cC2-10 alkenylxe2x80x9d, are mentioned, for example, vinyl, allyl, isopropenyl, 2-methylallyl, 1-propenyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 2-ethyl-1-butenyl, 2-methyl-1-butenyl, 3-methyl-2-butenyl, 1-pentenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 4-methyl-3-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl and 5-hexenyl. More specifically, C2-6 alkenyl (for example, vinyl, allyl, isopropenyl, 2-methylallyl, 2-methyl-1-propenyl, 2-methyl-2-propenyl and 3-methyl-2-butenyl) is frequently used for example. As said xe2x80x9cC2-10 alkynylxe2x80x9d are mentioned, for example, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 1-hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl and 5-hexynyl. Especially, C2-6 alkynyl (for example, ethynyl, 1-propynyl and 2-propynyl) is frequently used for example.
As said xe2x80x9calicyclic hydrocarbonxe2x80x9d are mentioned, for example, alicyclic hydrocarbon with 3 to 10 carbons (for example, C3-10 cycloalkyl, C3-10 cycloalkenyl and C5-10 cycloalkadienyl). As said xe2x80x9cC3-10 cycloalkylxe2x80x9d are mentioned, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl and cyclononyl). As said xe2x80x9cC3-10 cycloalkenylxe2x80x9d are mentioned, for example, 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl. As said xe2x80x9cC5-10 cycloalkadienylxe2x80x9d are mentioned, for example, 2,4-cyclopentadien-1-yl and 2,5-cyclohexadien-1-yl.
As said xe2x80x9carylxe2x80x9d are mentioned, for example, C6-14 aryl (for example, phenyl, naphtyl, anthryl, phenanthryl and acenaphthylenyl).
As said xe2x80x9caralkylxe2x80x9d are mentioned, for example, C7-14 aralkyl (for example, benzyl, phenethyl, 3-phenylpropyl, 4-phenylbutyl and 2-naphthylmethyl).
As the substituents that said xe2x80x9chydrocarbon groupxe2x80x9d may have are mentioned, for example, halogen atoms, nitro, cyano, imino, optionally substituted amino, optionally substituted hydroxy group, optionally substituted carboxy, cycloalkyl, cycloalkenyl and optionally substituted heterocyclic. The group containing aromatic ring in said xe2x80x9chydrocarbon groupxe2x80x9d may have alkyl, halogenoalkyl and optionally substituted aryl in addition to the substituents described before. These substituents may be substituted by 1 to 5 (preferably 1 to 3) said xe2x80x9chydrocarbon groupsxe2x80x9d.
As said xe2x80x9chalogen atomxe2x80x9d that is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned fluorine, chlorine, bromine and iodine for example.
As said xe2x80x9coptionally substituted amino groupxe2x80x9d that is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, (1) amino group that may have 1 to 2 substituents selected from (i) C1-6 alkyl that may be substituted by 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d (for example, methyl, ethyl, propyl, isopropyl and trifluoromethyl), phenyl and benzyl, (ii) formyl, C1-6 alkyl-carbonyl (for example, acetyl, propyonyl, butyryl), benzoyl, (iii) C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl) and C7-14 aralkyloxy-calbonyl (for example, benzyloxycarbonyl), (iv) sulfo group and C1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec-propylsulfonyl, butylsulfonyl and t-butylsulfonyl), and (v) C1-6 alkylaminocarbonyl (for example, methylaminocarbonyl, ethylaminocarbonyl, propylaminocarbonyl, butylaminocarbonyl and dimethylaminocarbonyl), and (2) pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl and 4-phenylpiperidyl.
As the substituents that said xe2x80x9coptionally substituted hydroxy groupxe2x80x9d may have are mentioned, for example, (i) optionally substituted C1-6 alkyl, (ii) optionally substituted C6-10 aryl, (iii) optionally substituted C7-14 aralkyl and (iv) acyl. As xe2x80x9cC1-6 alkylxe2x80x9d in said xe2x80x9coptionally substituted C1-6 alkylxe2x80x9d are mentioned, for example, methyl, ethyl, propyl, isopropyl, butyl and pentyl. Said xe2x80x9cC1-6 alkylxe2x80x9d may have 1 to 3 substituents selected from, for example, halogen atoms (for example, fluorine, chlorine, bromine and iodine), hydroxy, C1-6 alkoxy (for example, methoxy, ethoxy, propoxy and isopropoxy), formyl, C1-6 alkyl-carbonyl (for example, acetyl, propyonyl and butyryl), carboxyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl), amino, mono- or di-C1-6 alkylamino (for example, methylamino, ethylamino, dimethylamino and diethylamino), pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, carbamoyl, mono- or di-C1-6 alkyl-carbamoyl (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl), phenoxy, mono- or di-C1-6 alkyl-carbamoyloxy (for example, N-methylcarbamoyloxy, N-ethylcarbamoyloxy, N,N-dimethylcarbamoyloxy, N,N-diethylcarbamoyloxy), formylamino, C1-6 alkyl-carbonylamino (for example, acetylamino, propionylamino and butyrylamino), formyloxy and C1-6 alkyl-carbonyloxy (for example, acetoxy). As xe2x80x9cC6-10 arylxe2x80x9d in said xe2x80x9coptionally substituted C6-10 arylxe2x80x9d are mentioned, for example, phenyl and naphthyl. Said xe2x80x9cC6-10 arylxe2x80x9d may have 1 to 5 substituents selected from, for example, C1-6 alkyl (for example, methyl, ethyl, propyl and isopropyl) and halogeno-C1-6 alkyl (for example, C1-6 alkyl substituted by 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d, such as trifluoromethyl) in addition to the substituents that said xe2x80x9cC1-6 alkylxe2x80x9d may have. As said xe2x80x9coptionally substituted C7-14 aralkylxe2x80x9d are mentioned, for example, benzyl and phenethyl. As said substituents that xe2x80x9cC7-14 aralkylxe2x80x9d may have are mentioned those that said xe2x80x9cC6-10 arylxe2x80x9d may have. The number of substituents is 1 to 5. As said xe2x80x9cacylxe2x80x9d are mentioned, for example, formyl, C1-6 alkyl-carbonyl (for example, acetyl, propyonyl, butyryl and t-butylcarbonyl), benzoyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl), benzyloxycarbonyl, C1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec-propylsulfonyl, butylsulfonyl and t-butylsulfonyl), carbamoyl and mono- or di-C1-6 alkyl-carbamoyl (for example, N-methylcarbamoyl, N-ethylcarbamoyl, N,N-dimethylcarbamoyl and N,N-diethylcarbamoyl). These may have 1 to 3 substituents selected from, for example, halogen atoms (for example, fluorine, chlorine, bromine and iodine), hydroxy, C1-6 alkoxy (for example, methoxy, ethoxy, propoxy and isopropoxy), formyl, C1-6 alkyl-carbonyl (for example, acetyl, propyonyl and butyryl), carboxyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl), amino group, mono- or di-C1-6 alkylamino group (for example, methylamino, ethylamino, dimethylamino and diethylamino), pyrrolidinyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, 4-benzyloxycarbonylpiperidyl, carbamoyl, mono- or di-C1-6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl), phenoxy, mono- or di-C1-6 alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and diethylcarbamoyloxy), formylamino, C1-6 alkyl-carbonylamino group (for example, acetylamino, propyonylamino and butyrylamino), formyloxy and C1-6 alkyl-carbonyloxy (for example, acetoxy).
As the substituents that said xe2x80x9coptionally substituted carboxylxe2x80x9d that is the substitutent of said xe2x80x9chydrocarbon group.xe2x80x9d may have are mentioned, for example, C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl , butyl and t-butyl), benzyl and mono- or di-C1-6 alkylamino group (for example, methylamino, ethylamino, dimethylamino and diethylamino).
As said xe2x80x9ccycloalkylxe2x80x9d which is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, C3-6 cycloalkyl such as cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
As said xe2x80x9ccycloalkenylxe2x80x9d which is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, C3-6 cycloalkenyl such as 1-cyclobuten-1-yl, 1-cyclopenten-1-yl, 2-cyclopenten-1-yl, 3-cyclopenten-1-yl, 2-cyclohexen-1-yl and 3-cyclohexen-1-yl.
As xe2x80x9cheterocyclic ringxe2x80x9d in said xe2x80x9coptionally substituted heterocyclic ringxe2x80x9d that is the substituents of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, 5- or 6-membered monocyclic heterocyclic ring having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur in addition to carbon atom (for example, furyl, thienyl, pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, furazanyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, triazinyi, oxylanyl, azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, tetrahydrofuranyl, thiolanyl, piperidyl, tetrahydro-pyranyl, morpholinyl, thiomorpholinyl and piperadinyl), and benzene ring, bi- or tri-cyclic condensed heterocyclic ring which is formed by the condensation of above-described xe2x80x9c5- or 6-membered monocyclic heterocyclic ringxe2x80x9d (for example, benzofuranyl, isobenzofuryl, benzo[b]thienyl, indolyl, isoindolyl, 1H-indazolyl, benzimidazolyl, benzoxazolyl, 1,2-benzoisoxazolyl, benzthiazolyl, 1,2-benzoisothiazolyl, lH-benzotriazolyl, quinolyl, isoquinolyl, cinnolinyl, quinazolinyl, qunoxalinyl, phthalazinyl, naphthyldinyl, purinyl, puteridinyl, carbazolyl, xcex1-carbolinyl, xcex2-carbolinyl, xcex3-carbolinyl, acridinyl, phenoxazinyl, phenothiazinyl, phenazinyl, phenoxanthinyl, thianthrenyl, phenanthridinyl, phenanthrolinyl, indolidinyl, pyrrolo[1,2-b]pyridazinyl, pyrazolo[1,5-a]pyridyl, imidazo[1,2-a]pyridyl, imidazo[1,5-a]pyridyl, imidazo[1,2-a]pyridazinyl, imidazo[1,2-a]pyrimidinyl, 1,2,4-triazolo[4,3-a]pyridyl, 1,2,4-triazolo[4,3-b]-pyridazinyl, isochromanyl, chromanyl, indolinyl and isoindolinyl). As the substituents which said xe2x80x9cheterocyclic ringxe2x80x9d may have are mentioned, for example, oxo and pyrrolidinyl, in addition to the same substituents as those for said xe2x80x9caromatic hydrocarbon groupxe2x80x9d in ring A. Said xe2x80x9cheterocyclic ringxe2x80x9d may have 1 to 4 substituents selected from the substituents mentioned above,
As said xe2x80x9calkylxe2x80x9d which is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, C1-6 alkyl such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl and t-butyl.
As said xe2x80x9chalogenoalkylxe2x80x9d which is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, C1-6 alkyl substituted by 1 to 5 halogen atoms (for example, fluorine, chlorine, bromine and iodine) (for example, trifluoromethyl and trichloromethyl).
As xe2x80x9carylxe2x80x9d in said xe2x80x9coptionally substituted arylxe2x80x9d which is the substituent of said xe2x80x9chydrocarbon groupxe2x80x9d are mentioned, for example, C6-14 aryl such as phenyl, naphthyl, 2-biphenyl, 3-biphenyl, anthryl, phenanthryl and acenaphthylenyl. Said xe2x80x9cphenylxe2x80x9d, may have 1 to 5 substituents which are selected from, for example, halogen atoms (for example, fluorine, chlorine, bromine and iodine), C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl and t-butyl), halogeno-C1-6 alkyl (for example, C1-6 alkyl substituted by 1 to 5 said xe2x80x9chalogen atomsxe2x80x9d such as trifluoromethyl), C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, isopropoxy and t-butoxy), C7-14 aralkyloxy (for example, benzyloxy), hydroxy, amino, mono- or di-C1-6 alkylamino (for example, methylamino, ethylamino, dimethylamino and diethylamino), carboxy, C1-6 alkyl-carbonyl (for example, acetyl, propyonyl and butyryl), C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl), nitro and cyano.
As xe2x80x9coptionally substituted heterocyclic ringxe2x80x9d represented by R1 is used the same substituent as xe2x80x9coptionally substituted heterocyclic ringxe2x80x9d exemplified as the substituent on above xe2x80x9chydrocarbon groupxe2x80x9d.
Preferable examples of R1 are a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C6-14 aryl group or a C7-14 aralkyl group, which may be substituted with (1)halogen, (2)nitro, (3)amino which may have 1 to 2 substituents selected from C1-6 alkyl which may be substituted with C1-6 alkyl-carbonyl, benzyloxycarbonyl and C1-6 alkylsulfonyl, (4)hydroxy which may be substituted with (i)C1-6 alkyl which may be substituted with hydroxy, C1-6 alkyl-carbonyl, carboxy or C1-6 alkoxy-carbonyl, (ii)phenyl which may be substituted with hydroxy, (iii)benzoyl or (iv)mono- or di-C1-6 alkylamino-carbonyl, (5)C3-6 cycloalkyl, (6)phenyl which may be substituted with hydroxy or halogeno-C1-6 alkyl, or (7)thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl, and more preferably, a C1-6 alkyl group or a C7-14 aralkyl group, which may be substituted with hydroxy, phenyl or amino which may be substituted with C1-6 alkyl-carbonyl or C1-6 alkylsulfonyl.
Preferable position of substituents for aralkyl group represented by R1 is para-position.
In the formula mentioned above, R stands for an amino group that may be substituted. As said xe2x80x9coptionally substituted amino groupxe2x80x9d are mentioned, for example, (i) unsubstituted amino, (ii) optionally substituted hydrocarbon group, optionally substituted heterocyclic ring and amino group having 1 to 2 substituents selected from acyl groups, and (iii) optionally substituted nitrogen-containing heterocyclic ring.
As said xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d, the same substituent as said xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1 is frequently used for example.
As said xe2x80x9cheterocyclic ring which may have substituentsxe2x80x9d is used the same substituent as xe2x80x9cheterocyclic ring which may have substituentsxe2x80x9d represented by R1.
As said xe2x80x9cacyllxe2x80x9d are mentioned, for example, formyl, C1-6 alkyl-carbonyl (for example, acetyl, propionyl and butyryl), benzoyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl), C7-14 aralkyloxy-carbonyl (for example, benzyloxycarbonyl), piperidin-4-ylcarbonyl, C1-6 alkylsulfonyl (for example, methylsulfonyl, ethylsulfonyl, propylsulfonyl, sec-propylsulfonyl, butylsulfonyl and t-butylsulfonyl), carbamoyl and mono- or di-C1-6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl). These may have 1 to 3 substituents which are selected from, for example, halogen atoms (for example, fluorine, chlorine, bromine and iodine), hydroxy, C1-6 alkoxy (for example, methoxy, ethoxy, propoxy and isopropoxy), formyl, C1-6 alkyl-carbonyl (for example, acetyl, propionyl and butyryl), carboxy, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl), amino, mono- or di-C1-6 alkylamino (for example, methylamino, ethylamino, dimethylamino and diethylamino), pyrrolidinyl, piperidyl, morphorinyl, thiomorphorinyl, 4-methylpiperidyl, 4-phenylpiperidyl, carbamoyl, mono- or di-C1-6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl), phenoxy, mono- or di-C1-6 alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and diethylcarbamoyloxy), formylamino, C1-6 alkyl-carbonylamino (for example, acetylamino, propionylamino and butyrylamino), formyloxy and C1-6 alkyl-carbonyloxy (for example, acetoxy).
As xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d in said xe2x80x9coptionally substituted nitrogen-containing heterocyclic ring that may have substituentsxe2x80x9d are mentioned, for example, 5- to 7-membered nitrogen-containing heterocyclic rings having 1 to 4 hetero atoms selected from nitrogen, oxygen and sulfur other than nitrogen with a bond (for example, 1-imidazolyl, 1-pyrazolyl, 1-pyrrolyl, 1-pyrrolidinyl, 1-piperidyl, morpholinyl, thiomorpholinyl) or 5 to 7-membered nitrogen-containing heterocyclic rings condensed by benzene or pyridine (for example, 1-benzimidazolyl, 1,2,3,4-tetrahydroisoquinolin-2-yl, 1,2,3,4-tetrahydro-quinolin-1-yl and 1-indolyl).
As the substituent that said xe2x80x9cnitrogen-containing heterocyclic ringxe2x80x9d may have is used the same substituent as the substituent that said xe2x80x9caromatic hydrocarbon groupxe2x80x9d in ring A may have. They are preferably halogen atoms (for example, fluorine, chlorine, bromine and iodine), C1-6 alkyl (for example, methyl, ethyl, propyl, butyl, sec-butyl, t-butyl and isopropyl) and C1-6 alkoxy (for example, methoxy, ethoxy, propoxy, butoxy, sec-butoxy, t-butoxy and isopropoxy). The number of the substituents is 1 to 5.
Preferable example of R2 are an unsubstituted amino group, a piperidyl group or an amino group which have 1 to 2 substitutents selected from benzyl, C1-6 alkyl which may be substituted with amino or phenyl, mono- or di-C1-6 alkyl-carbamoyl, C1-6 alkoxy-carbonyl, C1-6 alkyl-sulfonyl, piperidylcarbonyl and C1-6 alkyl-carbonyl which may be substituted with halogen or amino and more preferably, an unsubstituted amino group.
In the formula mentioned above, E represents a bond, xe2x80x94CON(Ra)xe2x80x94, xe2x80x94N(Ra)COxe2x80x94, 
xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94N(Rd)COOxe2x80x94, xe2x80x94N(Re)SO2xe2x80x94, xe2x80x94COOxe2x80x94, xe2x80x94N(Rf)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94SOxe2x80x94 to xe2x80x94SO2xe2x80x94 (Ra, Rb, Rc, Rd, Re and Rf represent hydrogen or optionally substituted hydrocarbon groups, and hydrogen or C1-6 alkyl (for example, methyl) is preferably used, especially hydrogen is frequently used, as Ra, Rb, Rc, Rd, Re and Rf).
As said xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d is preferably used, for example, the same hydrocarbon group as the above-described xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R1.
Preferable example of E are a bond, xe2x80x94CON(Ra)xe2x80x94, xe2x80x94N(Ra)COxe2x80x94, xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94COOxe2x80x94, 
(in which Ra, Rb and Rc stands for the same as described above and preferably, a hydrogen atom or a C1-6 alkyl group), xe2x80x94CON(Ra)xe2x80x94 (in which Ra stands for the same as described above and preferably, a hydrogen atom or a C1-6 alkyl group)is preferably used. Especially, xe2x80x94CONH is frequently in use.
In the formula mentioned above, L stands for a divalent group, As said xe2x80x9cdivalent groupxe2x80x9d are mentioned, for example, divalent optionally substituted hydrocarbon groups which may be mediated by xe2x80x94Oxe2x80x94 to xe2x80x94Sxe2x80x94.
L is preferably an optionally substituted divalent hydrocarbon group, for example. Especially, optionally substituted C1-6 alkylene is frequently used.
As said xe2x80x9coptionally substituted divalent hydrocarbon groupxe2x80x9d is used the same hydrocarbon group as the above-described xe2x80x9coptionally substituted divalent hydrocarbon groupxe2x80x9d represented by D. As xe2x80x9cC1-6 alkylene groupxe2x80x9d in xe2x80x9coptionally substituted C1-6 alkylenexe2x80x9d are mentioned, for example, methylene, ethylene, propylene and butylene. Said xe2x80x9cC1-6 alkylenexe2x80x9d may have 1 to 5 C1-6 alkyl groups (for example, methyl, ethyl, propyl, isopropyl and butyl) for example.
Preferable examples of L are a C1-6 alkylene group which may be mediated by xe2x80x94Oxe2x80x94 and may be substituted with C1-6 alkyl and more preferably, a C1-6 alkylene group(for example, preferably methylene).
In the formula mentioned above, X stands for two hydrogen atoms, an oxygen atom or a sulfur atom, preferably an oxygen atom or a sulfur atom. Especially, oxygen atom is frequently used.
In the formula mentioned above,  stands for a single or a double bond. Preferably, a single bond is frequently used.
In the formula mentioned above, Y stands for nitrogen atom when  represents a double bond, and oxygen, xe2x80x94N(R4)xe2x80x94 (in which R4 stands for a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O)n (in which n is 0, 1 or 2) when  represents a single bond.
As said xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d represented by R4is used the same group as said xe2x80x9coptionally substituted hydrocarbon groupxe2x80x9d described in R1.
As said xe2x80x9cacylxe2x80x9d represented by R4 are mentioned, for example, formyl, C1-6 alkyl-carbonyl (for example, acetyl, propionyl and butyryl), benzoyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl, butoxycarbonyl and t-butoxycarbonyl), benzyloxycarbonyl, C1-6 alkylsulfonyl (for example, methylsulfonyl, ethyl-sulfonyl, propylsulfonyl, sec-propylsulfonyl, butysulfonyl and t-butylsulfonyl), carbamoyl and mono- or di-C1-6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl). They may have 1 to 3 substituents selected from, for example, halogen atoms (for example, fluorine, chlorine, bromine and iodine), hydroxy, C1-6 alkoxy (for example, methoxy, ethoxy, propoxy and isopropoxy), formyl, C1-6 alkyl-carbonyl (for example, acetyl, propionyl and butyryl), carboxyl, C1-6 alkoxy-carbonyl (for example, methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, sec-propoxycarbonyl and butoxycarbonyl), amino, mono- or di-C1-6 alkylamino (for example, methylamino, ethylamino, dimethylamino and diethylamino), pyrrolidyl, piperidyl, morpholinyl, thiomorpholinyl, 4-methylpiperidyl, 4-phenylpiperidyl, carbamoyl, mono- or di-C1-6 alkyl-carbamoyl (for example, methylcarbamoyl, ethylcarbamoyl, dimethylcarbamoyl and diethylcarbamoyl), phenoxy, mono- or di-C1-6 alkyl-carbamoyloxy (for example, methylcarbamoyloxy, ethylcarbamoyloxy, dimethylcarbamoyloxy and diethylcarbamoyloxy), formylamino, C1-6 alkyl-carbonylamino (for example, acetylamino, propionylamino and butyrylamino), formyloxy and C1-6 alkyl-carbonyloxy (for example, acetoxy).
As R4 is preferably used, for example, hydrogen or C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl and butyl).
Preferable examples of Y is a nitrogen atom when  is a double bond, or an oxygen atom, xe2x80x94N(R4)xe2x80x94 (in which R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O), (in which n is 0, 1 or 2) when  is a single bond, and preferably, an oxygen atom when  is a single bond.
Preferable examples of compounds of the formula (I) or a salt thereof include compounds wherein ring A is a benzene ring which may be substituted with halogen, hydroxy, C1-6 alkoxy, halogeno-C1-6 alkoxy, C7-14 aralkyloxy, benzoyl-C1-6 alkoxy, hydroxy-C1-6 alkoxy, C1-6 alkoxy-carbonyl-C1-6 alkoxy, C3-14 cycloalkyl-C1-6 alkoxy, imidazol-1-yl-C1-6 alkoxy, C7-14 aralkyloxy-carbonyl-C1-6 alkoxy or hydroxyphenyl-C1-6 alkoxy,
ring B is a benzene ring or a thiophene ring, which may be substituted with C1-6 alkoxy, or a tetrahydroisoquinoline ring by combining with R2,
Z is a C6-14 aryl group, a C3-10 cycloalkyl group, a piperidyl group, a thienyl group, a furyl group, a pyridyl group, a thiazolyl group, an indolyl group or a C1-6 alkyl group, which may have 1 to 3 substituents selected from halogen, formyl, halogeno-C1-6 alkyl, C1-6 alkoxy and C1-6 alkoxy-carbonyl, oxo and pyrrolidinyl,
D is a C1-6 alkylene group,
G is a bond or a C1-6 alkylene group which may have phenylene and which may be substituted with phenyl,
R1 is a hydrogen atom, a C1-6 alkyl group, a C2-6 alkenyl group, a C6-14 aryl group or a C7-14 aralkyl group, which may be substituted with (1)halogen, (2)nitro, (3)amino which may have 1 to 2 substituents selected from C1-6 alkyl which may be substituted with C1-6 alkyl-carbonyl, benzyloxycarbonyl and C1-6 alkylsulfonyl, (4)hydroxy which may be substituted with (i)C1-6 alkyl which may be substituted with hydroxy, C1-6 alkyl-carbonyl, carboxy or C1-6 alkoxy-carbonyl, (ii)phenyl which may be substituted with hydroxy, (iii)benzoyl or (iv)mono- or di-C1-6 alkylamino-carbonyl, (5)C3-6 cycloalkyl, (6)phenyl which may be substituted with hydroxy or halogeno-C1-6 alkyl, or (7)thienyl, furyl, thiazolyl, indolyl or benzyloxycarbonylpiperidyl,
R2 is (1) an unsubstituted amino group, (2) a piperidyl group or (3) an amino group which have 1 to 2 substitutents selected from (i) benzyl, (ii) C1-6 alkyl which may be substituted with amino or phenyl, (iii) mono- or di-C1-6 alkyl-carbamoyl, (iv) C1-6 alkoxy-carbonyl, (v) C1-6 alkyl-sulfonyl, (vi) piperidylcarbonyl and (vii) C1-6 alkyl-carbonyl which may be substituted with halogen or amino,
E is a bond, xe2x80x94CON(Ra)xe2x80x94, xe2x80x94N(Ra)COxe2x80x94, xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94COOxe2x80x94, 
in which Ra, Rb and Re is a hydrogen atom or a C1-6 alkyl group,
L is a C1-6 alkylene group which may be mediated by xe2x80x94Oxe2x80x94 and may be substituted with C1-6 alkyl,
X is an oxygen atom, and
 is a single bond or a double bond, and
Y is a nitrogen atom when  is a double bond, or an oxygen atom, xe2x80x94N(R4)xe2x80x94 (in which R4 is a hydrogen atom, an optionally substituted hydrocarbon group or an acyl group) or S(O)n (in which n is 0, 1 or 2) when  is a single bond.
More preferable examples of compounds of the formula (I) include compounds wherein ring A is a benzene ring which may be substituted with halogen, hydroxy or C1-6 alkoxy,
ring B is a benzene ring or a thiophene ring, or a tetrahydroisoquinoline ring by combining with R2,
Z is a phenyl group which may be substituted with halogen,
D is a C1-6 alkylene group,
G is a C1-6 alkylene group,
R1is a C1-6 alkyl group or a C7-14 aralkyl group, which may be substituted with hydroxy, phenyl or amino which may be substituted with C1-6 alkyl-carbonyl or C1-6 alkylsulfonyl,
R2 is an unsubstituted amino group,
E is xe2x80x94CONHxe2x80x94,
L is a C1-6 alkylene group,
X is an oxygen atom, and
Y is an oxygen atom when  is a single bond. iMore preferable examples of compounds of the formula (I) include compounds wherein the substituent (xe2x80x94Dxe2x80x94Exe2x80x94Gxe2x80x94Z) at 3-position of benzoxazepine ring is S-configration, and relative configration between the substituent at 3-position and the substituent (ring B) at 5-position is trans.
Most preferable examples of compounds of the formula-(I) or a salt thereof include
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
(3S,5S)-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-neopentyl-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-[2-(4-biphenyl)ethyl]-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(4-aminomethylphenyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(2-aminomethylthiophen-5-yl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-[3-[(1-amino-1-methyl)ethyl]phenyl]-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-(4-hydroxybenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-1(4-acetylaminobenzyl)-5-(3-aminomethylphenyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-(4-methanesulfonylaminobenzyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-hydroxybenzyl)-7-methyloxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-[4-[(1-amino-1-methyl)ethyl]phenyl]-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-7-chloro-1-[2-(4-hydroxyphenyl)ethyl]-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof,
3,5-trans-N-(2-fluorobenzyl)-5-(3-aminomethylphenyl)-1-(4-biphenylmethyl)-7-hydroxy-2-oxo-1,2,3,5-tetrahydro-4,1-benzoxazepine-3-acetamide or a salt thereof, and
3,5-trans-N-(2-fluorobenzyl)-1-(4-biphenylmethyl)-7-chloro-2-oxo-1,2,3,5-tetrahydro-5-(1,2,3,4-tetrahydroisoquinolin-5-yl)-4,1-benzoxazepine-3-acetamide or a salt thereof.
The compound or a salt thereof represented by the formula (I) may be manufactured using the following method or a method corresponding thereto.
In the compounds represented by the formula (I), a compound represented by the formula (Ia): 
wherein, R2a stands for the group having a protecting group (for example, t-butoxycarbonyl, benzyloxycarbonyl and trityl) in the above-described R2, and the other symbols have the same meaning as described above, or a salt thereof, can be produced by allowing a compound represented by the formulae (IIIa), (IIIb) or (IIIc) obtained by the methods (Method A), (Method B) and (Method C) shown below as intermediate to react with the a compound represented by the formula (IV), (IVxe2x80x2) or (IVxe2x80x3): 
wherein the symbols have the same meaning as described above or a salt thereof. 
Le stands for an elimination radical (for example, chlobrine, bromine, iodine, methylsulfonyloxy and toluenesulfonyloxy); R1a stands for an optionally substituted hydrocarbon group represented by RI excluding its methylene group and the other symbols stand for the same meaning as described above. 
These symbols have the same meaning as described above.
In the reaction of the compound represented by the formula (IIIa-1) or a salt thereof in the above-mentioned (Method A) to give the compound represented by the formula-(IIIa-2) or a salt thereof, the reduction reaction of the carbonyl in the compound represented by the formula (IIIa-1) or a salt thereof may be carried out by treating the compound, for example, with a metal-hydrogen complex (for example, aluminum lithium hydride, aluminum sodium hydride, triethoxy aluminum sodium hydride and boron sodium hydride), in a solvent, for example, selected from proton solvents (for example, methanol, ethanol, propanol and butanol), or non-proton solvents (for example, ethylether, tetrahydrofuran and dioxane). Such a metal-hydrogen complex is used in a quantity of approximately 0.3 to 5 mol equivalent, preferably approximately 0.5 to 2 mol per 1 mol of the compound represented by the formula (IIIa-1) or a salt thereof. The reaction temperature is about xe2x88x9220 to 100xc2x0 C., preferably about 20 to. 50xc2x0 C., and the reaction time is about 0.5 to 24 hours.
The reaction of the compound represented by the formula (IIIa-2) or a salt thereof in the above-mentioned (Method A) to give the compound represented by the formula (IIIa-5) or a salt thereof may be carried out in solvent selected, for example, from ether solvents (for example, diethyl ether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol and propanol), acetone and dimethylformamide optionally in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride). For this reaction, approximately 1 to 10 mol equivalent, preferably approximately 1 to 2 mol equivalent of the compound represented by the formula (IIIa-3) or a salt thereof is used for 1 mol of the compound represented by the formula (IIIa-2) or a salt thereof. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. The compound represented by the formula (IIIa-5) or a salt thereof can be manufactured by subjecting the compound represented by the formula (IIIa-2) or a salt thereof and the compound represented by the formula (IIIa-4) or a salt thereof to catalytic reduction and reductive amidation using boron sodium hydride or sodium boron cyanohydride, for example, in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol: solvents (for example, methanol, ethanol, propanol and butanol). At that time approximately 1 to 10 mol equivalent, preferably approximately 0.5 to 1 mol equivalent of the compound represented by the formula (IIIa-4) or a salt thereof is used to 1 mol of the compound represented by the formula (IIIa-2) or a salt thereof. The reaction temperature at that time is about 0 or 100xc2x0 C., preferably about 10 to 70xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.
The reaction of the compound represented by the formula (IIIa-5) or a salt thereof in the above-described (Method A) with fumaric chloride monoethyl ester and the reaction of the compound represented by the formula (IIIa-5) or a salt thereof in the above-described (Method B) with the compound represented by the formula (IIIb-1) or a salt thereof can be carried out using a per se known acylation reaction. This acylation reaction may be carried out, for example, in a solvent selected from ether solvents (for example, diethylether, tetrahydrofuran and dioxane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform and.carbon tetrachloride), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), dimethylformamide, dimethylsulfoxide ester solvents (for example, ethyl acetate, methyl acetate) optionally in the presence of water and a base (for example, 4-dimethylaminopyridine, triethylamine, triethylene-diamine, tetramethylethylenediamine, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride). At that time, approximately 1 to 10 mol equivalent, preferably approximately 1 to 3 mol equivalent of the compound represented by the formula (IIIb-1) or a salt thereof and an acid chloride (for example, fumaric chloride monoethyl ester) are used for 1 mol of the compound represented by the formula (IIIa-5) or a salt thereof. The reaction temperature at that time is about xe2x88x9250 to 100xc2x0 C., preferably about 0 to 50xc2x0 C. The reaction time is about 1 to 48 hours, preferably about 5 to 10 hours.
The cyclization of the compound represented by the formula (IIIa-6) or a salt thereof in the above-described (Method A) to give the compound represented by the formula (IIIa-7) or a salt thereof may be carried out, for example, in a solvent selected from ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), acetone and dimethylformamide optionally in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride). At that time, approximately 1 to 5 mol equivalent, preferably approximately 1 to 2 mol equivalent of these bases is used for 1 mol of the compound represented by the formula (IIIa-6) or a salt thereof. The reaction temperature at that time is about xe2x88x9220 to 200xc2x0 C., preferably about 20 to 100xc2x0 C. The reaction time is about 1 to 20 hours, preferably about 2 to 5 hours.
The cyclization of the compound represented by the formula (IIIb-2) in the above-described (Method B) to give the compound represented by the formula (IIIb-3) or a salt thereof may be carried out, for example, in a solvent selected from ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), acetone, dimethylformamide optionally in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and potassium hydride). At that time, approximately 1 to 5 mol equivalent, preferably approximately 1 to 2 mol equivalent of these bases is used for 1 mol of the compound represented by the formula (IIIb-2) or a salt thereof. The reaction temperature is about xe2x88x9220 to 100xc2x0 C., preferably about 20 to 100xc2x0 C. Reaction time is about 1 to 20 hours, preferably about 2 to 5 hours.
The compounds represented by the formula (IIIa) or a salt thereof in the above-described (Method A) and the compounds represented by the formula (IIIb) or a salt thereof in the above-described (Method B) are m; manufactured by treating the compound represented by the formula of either (IIIa-7) or (IIIb-3) or a salt thereof with an acid or a base. Namely, the compound can be produced from the compound represented by the formula (IIIa-7) or (IIIb-3) or a salt thereof in an aqueous solution of, for example, a mineral acid (for example, nitric acid, hydrochloric acid, hydrobromic acid, hydroiodic acid and sulfuric acid) or an alkaline metal hydroxide (for example, sodium hydroxide, barium hydroxide and-lithium hydroxide) at the temperature of about 0 to 150xc2x0 C., preferably about 20 to 50xc2x0 C. At that time, the intensity of the acid and the base is about 1 to 10 normal, preferably about 4 to 10 normal. The reaction time at that time is about 1 to 24 hours, preferably about 2 to 10 hours.
The compound represented by the formula (Ia) or a salt thereof can be produced by allowing the compound represented by the formula (IIIa) or (IIIb) or a salt thereof to react with the compound represented by the formula (IV), (IVxe2x80x2) or (IVxe2x80x3) or a salt thereof in a solvent optionally in the presence of a base using a condensing agent. The solvent used therein is selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform and carbon tetrachloride), acetonitrile and dimethylformamide. As the base used therein are mentioned, for example, triethylamine, 4-dimethylaminopyridine, triethylenediamine and tetramethylethylenediamine. As the condensing agent are mentioned, for example, condensing agents used for peptide synthesis. More specifically, dicyclohexylcarbodiimide, diethyl cyanophosphate and 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide are frequently used for example. At that time, approximately 0.5 to 2 mol equivalent, preferably approximately 1 to 1.2 mol equivalent of the compound represented by the formula (IV) or a salt thereof is used for 1 mol of the compound represented by the formula (IIIa) or (IIIb) or a salt thereof, and about 0.5 to 5 mol equivalent, preferably about 1 to 2 mol equivalent of the condensing agent is used. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 0.5 to 24 hours, preferably about I to 5 hours. In the compounds represented by the formula (I), a compound shown by the formula (Ib): 
wherein the symbols have the same meaning as described above, or a salt thereof can be produced by allowing the compound represented by the formula (IIIc) or a salt thereof obtained by (Method C) and (Method D) described below as the intermediate to react with a compound represented by the formula (IV). 
Le1 has the same meaning as Le. However, Le1 and Le are not the same at the same time. The other symbols have the same meaning as described above or a salt thereof. 
These symbols have the same meaning as described above.
The production of the compound represented by the formula (IIIc-1) or a salt thereof from the compound represented by the.formula (IIIa-1) or a salt thereof in the above-described (Method C) is carried out by the method similar to that for producing the compound represented by the formula (IIIa-5) or a salt thereof by, for example, allowing the compound represented by the formula (IIIa-2) or a salt thereof shown in the above-described (Method A) to react with the compound represented by the formula (IIIa-3) or (IIIa-4) or a salt thereof. The production of the compound represented by the formula (IIIc-3) or a salt thereof from the compound represented by the formula (IIIc-1) or a salt thereof, and the compound represented by the formula (IIId-1) or a salt thereof from the compound represented by the formula (IIIa-1) or a salt thereof in the above-described (Method C) and (Method D) is carried out in solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform), acetonitrile and dimethylformamide using condensing agent (for example, diethyl cyano-phosphate and dicyclohexylcarbodiimide) optionally in the presence of a base (for example, triethylamine, 4-dimethylaminopyridine and N-methylpiperidine). Approximately 1 to 5-mol equivalent, preferably 1 to 1.5 mol equivalent of the compound represented by the formula (IIIc-2) or a salt thereof is used for 1 mol of the compound represented by the formula (IIIc-1) or (IIIa-1) or a salt thereof. The reaction temperature at that time is about 0 to 100 IC, preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 2 to 5 hours. At that time about 1 to 5 mol equivalent, preferably about 1 to 2 mol equivalent of a condensing agent is used for 1 mol of the compound represented by the formula (IIIc-1) or (IIIa-1).
The production of the compound represented by the formfula (IIIc-4) or a salt thereof from the compound represented by the formula (IIIc-3) or a salt thereof in the above-described (Method C) or the compound represented by the formula (IIId-2) or a salt thereof from the compound represented by the formula (IIId-1) or a salt thereof in the above-described (Method D) is carried out by a per se known method in a solvent selected, for example, from ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), haloid solvents (for example, dichlormethane, dichlorethane and chloroform), acetone, acetonitrile and dimethylformamide. When Le1 is carbobenzyloxy, for example, Le1 is liberated by catalytic reduction using, for example paradium and platinum, and when Le1 is t-butoxycarbonyl, for example, Le1 is liberated by dissolving in an acid (for example, hydrochloric acid, hydrobromic acid and trifluoroacetic acid) before the above production is carried out from the thus Le1-liberated compound in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), acetonitrile and dimethylformamide optionally in the presence of an acid (for example, hydrochloric acid, hydrobromic acid, propionic acid, methanesulfonic acid, toluenesulfonic acid and sulfuric acid). The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 30 to 70xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. For the production of the compound represented by the formula (IIIc-4) or a salt thereof from the compound represented by the formula (IIId-2) in the above-described (Method D) is used a method similar to that for the reaction between the compound represented by the formula (IIIa-2) or a salt thereof in the above-described (Method A) and the compound represented by the formula (IIIa-3) or a salt thereof. Also, for the production of the compound represented by the formula (IIIc) or a salt thereof from the compound represented by the formula (IIIc-4) in the above-described (Method C) and (Method D) is used a method similar to that for the production of the compound represented by the formula (IIIa) or a salt thereof from the compound represented by the formula (IIIa-7) or a salt thereof in the above-described (Method A).
In the compounds represented by the formula (I), a compound represented by the formula (Ic): 
wherein the symbols have the same meaning as described above, or a salt thereof can.be produced by reducing the compound represented by the formula (Ib) or a salt thereof. Namely, the compound can be produced in a solvent selected from, for example water, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), haloid solvents (for example, dichlormethane, chloroform) using a reducing agent such as sodium boron hydride, aluminum lithium hydride and sodium boron cyanohydride. In this reaction, approximately 0.2 to 5 mol equivalent, preferably approximately 0.3 to 1 mol equivalent of the reducing agent is used for 1 mol of the compound represented by the formula (Ib) or a salt thereof. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 0.5 to 10 hours, preferably about 1 to 3 hours.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Id): 
wherein R4a stands for optionally substituted hydrocarbon group and the other symbols in the formula have the same meaning as described above, or a salt thereof is produced by the reaction between the compound represented by the formula (Ic) or a salt thereof, and a compound represented by the formula (IVa) or (IVb):
R4axe2x80x94Lexe2x80x83xe2x80x83(IVa) 
or 
R4aaxe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(IVb) 
wherein R4aa stands for optionally substituted hydrocarbon group and the other symbols in the formula have the same meaning as described above, or a salt thereof. For example, the reaction between the compound represented by the formula (Ic) or a salt thereof and the compound represented by the formula (Iva) or a salt thereof may be carried out by the method similar to that for the reaction between the compound represented by the formula (IIIa-2) or a salt thereof and the compound represented by the formula (IIIa-3) or a salt thereof in the above-described (Method A). Further, the reaction between the compound represented by the formula (Ic) or a salt thereof and the compound represented by the formula (IVb) or a salt thereof may be carried in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform), acetonitrile and dimethylformamide, optionally using a base. As the base used therein are mentioned organic bases such as triethylamine, 4-dimethylaminopyridine, triethylenediamine, and tetramethylethylenediamine. In this reaction approximately 0.5 to 3 mol equivalent, preferably approximately 1 to 1.5 mol equivalent of the compound represented by the formula (IVb) or a salt thereof is used for 1 mol of the compound represented by the formula (Ic). The reaction temperature at that time is about 0 to 150xc2x0 C., preferably about 30 to 100xc2x0 C. The reaction time is about 0.5 to 24 hours, preferably about 1 to 3 hours.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Ie): 
wherein the symbols have the same meaning as described above or a salt thereof is produced by, for example, introducing a compound represented by the formula (V): 
wherein the symbols have the same meaning as described above or a salt thereof to a compound represented by the formula (VI): 
wherein the symbols have the same meaning as described above or a salt thereof, and allowing this to react with a compound of the formula (VII):
Zxe2x80x94Gxe2x80x94COOHxe2x80x83xe2x80x83(VII) 
wherein the symbols have the same meaning as described above or a salt thereof.
The compound represented by the formula (VI) or a salt thereof can be produced by allowing the compound represented by the formula (V) or a salt thereof to react with diphenylphosphorylazide in solvent in the presence of a base and treating the obtained product in solvent with an acid. As the solvent used in the reaction between the compound of the formula (V) or a salt thereof with diphenylphosphorylazide are mentioned, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform) and dimethylformamide. As the base used therein are mentioned, for example, triethylamine, 4-dimethylaminopyridine, triethylenediamine and tetramethylene-diamine. In this reaction, approximately 1 to 10 mol equivalent, preferably approximately 1.5 to 3 mol equivalent of diphenylsulfonylazide is used for the compound of the formula (V). The reaction temperature at that time is about xe2x88x9220 to 50xc2x0 C., preferably about 0 to 20xc2x0 C. The reaction time is about 0.5 to 5 hours, preferably about 1 to 2 hours.
As the solvent used for treating the above reaction products with an acid are mentioned, for example, water, dioxane and dimethylformamide and as the acid used are mentioned mineral acids such as sulfuric acid, hydrochloric acid, nitric acid and hydrobromic acid. The reaction temperature at that time is about 20 to 200xc2x0 C., preferably about 50 to 100xc2x0 C. The reaction time is about 0.5 to 5 hours, preferably about 1 to 2 hours. The condensation reaction of the compound represented by the formula (VI) or a salt thereof with the compound represented by the formula (VII) or a salt thereof is conducted under conditions similar to that for the condensation reaction between, for example, the compound represented by the formula (IIIa) or (IIIb) or a salt thereof and the compound represented by the formula (IV) or a salt thereof to give the compound represented by the formula (Ia) or a salt thereof.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (If): 
wherein the symbols have the same meaning as described above, or a salt thereof, or a compound represented by the formula (Ig): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced under conditions similar to that for producing the compound represented by the formula (VI) or a salt thereof, for example, by allowing the compound represented by the formula (V) or a salt thereof to react with diphenylphosphorylazide to give an intermediate compound of the formula (VIII): 
wherein the symbols have the same meanig as described above and allowing this to react with a compound represented by the formula (IX) or (X):
Zxe2x80x94GAOHxe2x80x83xe2x80x83(IX) 
or 
Zxe2x80x94Gxe2x80x94NHRcxe2x80x83xe2x80x83(X) 
wherein the symbols have the same meaning as described above, or a salt thereof. The production may be carried out under conditions similar to the reaction between the compound represented by the formula (Ic) or a salt thereof and the compound represented by the formula (IVb) or a salt thereof.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Ih): 
wherein the symbols have the same meaning as described above or a salt thereof is produced by the reaction between the compound represented by the formula (VI) or a salt thereof and a compound represented by the formula (XI):
Zxe2x80x94SO2Clxe2x80x83xe2x80x83(XI) 
wherein the symbols have the same meaning as described above, or a salt thereof. This reaction may be carried out in a solvent selected from, for example, ether solvents (for example, dimethylether, tetrahydrofuran and dioxane), alcohol solvents (for example, methanol, ethanol, propanol and butanol), acetone and dimethylformamide optionally in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydride and triethylamine). In this reaction, approximatelyl to 10 mol equivalent, preferably approximately 1 to 2 mol equivalent of the compound represented by the formula (XI) or a salt thereof are used for 1 mol of the compound represented by the formula (VI). The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.
In the compounds represented by the formula (I), a compound represented by the formula (Ii): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by the reaction between the compound represented by the formula (V) or a salt thereof and a compound represented by the formula (XII):
Zxe2x80x94Gxe2x80x94OHxe2x80x83xe2x80x83(XII) 
described above, or a salt thereof. It can be produced, for example, by allowing the compound represented by the formula (V) or a salt thereof to react with the compound represented by the formula (XII) or a salt thereof using a condensing agent in a solvent optionally in the presence of a base. As the solvent used therein are mentioned, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), haloid solvents (for example, dichlormethane, dichlorethane, chloroform and carbon tetrachloride), acetonitrile and dimethylformamid. As the base used therein are mentioned, for example, triethylamine, 4-dimethylaminopyridine, triethylenediamine, tetramethylethylenediamine. As condensing agent used therein are mentioned, for example, a condensing agent used for the synthesis of a peptide, more specifically, dicyclohexylcarbodiimide, diethyl cyanophosphate and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide. In this reaction approximately 0.5 to 2 mol equivalent, preferably approximately 1 to 1.2 mol equivalent of the compound represented by the formula (XII) or a salt thereof and approximately 0.5 to 5 mol equivalent, preferably approximately 1 to 2 mol equivalent of the condensing agent are used for 1 mol of the compound represented by the formula (V) or a salt thereof. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 0.5 to 24 hours, preferably about 1 to 5 hours.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Ij): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by allowing a compound represented by the formula (XIII): 
wherein the symbols have the same meaning as described above or a salt thereof to react with a compound represented by the formula (XIV):
Zxe2x80x94Lexe2x80x83xe2x80x83(XIV) 
wherein the symbols have the same meaning as described above or a salt thereof. The compound represented by the formula (XIII) or a salt thereof can be produced by treating the compound represented by the formula (V) or a salt thereof in a solvent selected from, for example, proton solvents (for example, methanol, ethanol, propanol and butanol) and non-proton solvents (for example, ethylether, tetrahydrofuran and dioxane) with, for example, a metal-hydrogen complex (for example, aluminum lithium hydride, aluminum sodium hydride and boron sodium hydride). The metal-hydrogen complex is used in quantity of approximately 0.3 to 5 mol equivalent, preferably approximately 0.5 to 2 mol equivalent for 1 mol of the compound represented by the formula (V). The reaction temperature at that time is about xe2x88x9220 to 100xc2x0 C., preferably about 0 to 20xc2x0 C. The reaction time is about 0.5 to 10 hours, preferably about 1 to 3 hours.
As the solvent used in the reaction between the compound represented by the formula (XIII) or a salt thereof and the compound represented by the formula (XIV) or a salt thereof may be mentioned, for example, non-proton solvents (for example, ethylether, tetrahydrofuran, dioxane, acetonitrile and dimethylformamide) optionally using, for example, an inorganic base (for example,: sodium hydrogen carbonate, potassium hydrogen carbonate, sodium carbonate and potassium carbonate), an organic base (for example, triethylamine, 4-dimethylaminopyridine, triethylenediamine and tetramethylethylenediamine), sodium hydroxide and cesium fluoride. In this reaction, approximately 0.5 to 5 mol equivalent, preferably approximately 1 to 2 mol equivalent of the compound represented by the formula (XIV) or a salt thereof is used for 1 mol of the compound represented by the formula (XIII) or a salt thereof. The reaction temperature at that time is about 0 to 2000C, preferably about 20 to 100xc2x0 C. The reaction time is about 10 minutes to 5 hours, preferably about 30 minutes to 2 hours.
In the compounds represented by the formula (I) salts thereof, a compound represented by the formula (Ik): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by allowing a compound represented by the formula (XV): 
wherein Le2 is a halogen (for example, chlorine, bromine and iodine) and the other symbols have the same meaning as described above, or a salt thereof to react with a compound represented by the formula (XVI):
Zxe2x80x94SHxe2x80x83xe2x80x83(XVI) 
wherein the symbols have the same meaning as described above, or a salt thereof.
The compound represented by the formula (XV) or a salt thereof can be produced by, for example, diazotization of the compound represented by the formula (VI) or a salt thereof in, for example, hydrochloric acid, hydrobromic acid or hydroiodic acid with sodium nitrite followed by heating. The reaction temperature at that time is about 20 to 200xc2x0 C., preferably about 50 to 100xc2x0 C. The reaction time is about 5 minutes to 2 hours, preferably about 15 to 30 minutes. The reaction between the compound represented by the formula (XV) or a salt thereof and the compound represented by the formula (XVI) or a salt thereof may be carried out under conditions similar to that for production of the compound represented by the formula (Ij) or a salt thereof by reaction between the compound represented by the formula (XIII) or a salt thereof and the compound represented by the formula (XIV) or a salt thereof.
Of the compounds represented by formula (I) or salts thereof, a compound represented by the formula (Il): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by oxidizing the compound represented by the formula (Ik) or a salt thereof. In this reaction, approximately 1 to 5 mol equivalent, preferably approximately 2 to 3 mol equivalent of metachloroperbenzoic acid is used for 1 mol of the compound represented by the formula (Im) in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform), acetonitrile and dimethylformamide. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 0 to 30xc2x0 C. The reaction time is about 1 to 10 hours, preferably about 1 to 2 hours.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Im): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by allowing the compound represented by the formula (XIII) or a salt thereof to react with the compound represented by the formula (VII) or a salt thereof under conditions similar to that of the reaction of the compound represented by the formula (V) or a salt thereof and the compound represented by the formula (XII) or a salt thereof for the production of the compound represented by the formula (Ii) or a salt thereof.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (In): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by allowing the compound represented by the formula (XIII) or a salt thereof to react with a compound represented by the formula (XVII):
Zxe2x80x94Nxe2x95x90Cxe2x80x94Oxe2x80x83xe2x80x83(XVII) 
wherein the symbols have the same meaning as described above, or a salt thereof. As the solvent used in this reaction are mentioned, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), haloid solvents (for example, dichlormethane, dichlorethane and chloroform), acetonitrile and dimethylformamide. A base (for example, triethylamine, 4-dimethyl-aminopyridine, triethylenediamine, tetramethylethylenediamine) is optionally used. In this reaction, approximately 0.5 to 3 mol equivalent, preferably approximately 1 to 1.5 mol equivalent of the compound represented by the formula (XVII) or a salt thereof is used for 1 mol of the compound represented by the formula (XIII) or a salt thereof. The reaction temperature at that time is about 0 to 150xc2x0 C., preferably about 30 to 100xc2x0 C. The reaction time is about 0.5 to 24 hours, preferably about 1 to 3 hours.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Io): 
wherein E1 is xe2x80x94CON(Ra)xe2x80x94, xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94N(Rd)COOxe2x80x94 or xe2x80x94N(Re)SO2xe2x80x94 and the other symbols have the same meaning as described above, or a salt thereof is produced by allowing, when E1 is xe2x80x94CON(Ra)xe2x80x94 in the formula (Io), a compound represented by the formula (Iaa): 
wherein the symbols have the same meaning as described above, or a salt thereof, or a compound represented by the formula (Ibb): 
wherein the symbols have the same meaning as described above, or a salt thereof, or a compound represented by the formula (Idd): 
wherein the symbojshave the same meaning as described above, or a salt thereof to react with a compound represented by the formula (XIX):
Raxe2x80x94Lexe2x80x83xe2x80x83(XIX) 
wherein the symbols have the same meaning as described above, or a salt thereof.
This reaction is carried out in, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvents (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol and propanol), acetone and dimethylformamide, optionally in the presence of a base (for example, sodium hydrogen carbonate, potassium hydrogen carbonate, sodium hydrogen carbonate, potassium carbonate, sodium hydride and potassium hydride). In this reaction, approximately 1 to 10 mol equivalent, preferably approximately 1 to 2 mol equivalent of the compound of the formula (XIX) is used to react with 1 mol of the compound represented by the formula (Iaa), (Ibb) or (Idd) or a salt thereof. The reaction temperature at that time is about 0 to 100xc2x0 C., preferably about 20 to 50xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours. The compounds are produced, when E1 is xe2x80x94N(Rb)CON(Rc)xe2x80x94, xe2x80x94N(Rd)COOxe2x80x94 or xe2x80x94N(Re)SO2xe2x80x94 in the formula (Io), in a manner similar to that when E1 is xe2x80x94CON(Ra)xe2x80x94.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Ip): 
wherein R2b is a deprotected R2a and the other symbols have the same meaning as described above, or a salt thereof is produced by removing the protective group of a compound represented by the formula (Iq): 
wherein the symbols have the same meaning as described above, or a salt thereof by a per se known method.
The removal of the protective group, when the protective group is t-butoxycarbonyl, trityl and benzyloxycarbonyl, can be done by treating the compound with an acid such as hydrogen chloride, hydrogen bromide, hydrochloric acid, hydrobromic acid, nitric acid, sulfuric acid and trifluoroacetic acid in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane) and haloid solvents (for example, dichlormethane, dichlorethane and chloroform). Further, the removal of the protective group, when the protective group is benzyloxycarbonyl, can be done by hydrolyzing the compound by using, for example, a paradium catalyst (for example, metal paradium and paradium/charcoal) in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane) alcoholic solvents (for example, methanol, ethanol, propanol), dimethylformamide, acetic acid ethylester and acetic acid. In this reaction, the reaction temperature is about xe2x88x9220 to 100xc2x0 C., preferably about 0 to 30xc2x0 C. when treated with an acid. The reaction time is about 0.1 to 5 hours, preferably about 0.5 to 1 hours. In this reaction, the reaction temperature is xe2x88x9220 to 150xc2x0 C., preferably about 0 to 50xc2x0 C. when hydrolysis is conducted. The reaction time is about 0.1 to 10 hours, preferably about 0.5 to 3 hours. The hydrogen pressure is about 1 to 100.atmospheric pressures, preferably about 1 to 3 atmospheric pressures. The catalysts are used at this time in approximately 0.001 to 0.5 mol equivalent, preferably approximately 0.01 to 0.1 mol equivalent for 1 mol of the compound represented by the formula (Ia) or a salt thereof.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (Ir): 
wherein Y1 stands for oxygen or xe2x80x94N(R4a)xe2x80x94 (in which R4a stands for a hydrocarbon that may have substituents) and the other symbols have the same meaning as described above or a salt thereof is produced by allowing a compound represented by the formula (Is): 
wherein the symbols have the same meaning as described above, or a salt thereof to react with a compound represented by the formula (XX) or (XXI):
R2cxe2x80x94Lexe2x80x83xe2x80x83(XX) 
or 
R2dxe2x80x94Nxe2x95x90Cxe2x95x90Oxe2x80x83xe2x80x83(XXI) 
wherein each of R2c and R2d is an optionally substituted hydrocarbon group, an optionally substituted heterocyclic group or acyl and the other symbols have the same meaning as described above, or a salt thereof. The reaction between the compound represented by the formula (Is) or a salt thereof and the compound represented by the formula (XX) or a salt thereof can be done under conditions similar to that for the reaction between the compound represented by the formula (IIIa-2) or a salt thereof and the compound represented by the formula (IIIa-3) or a salt thereof in the above-described (Method A). Further, the reaction between the compound represented by the formula (Is) or a salt thereof and the compound represented by the formula (XXI) or a salt thereof can be done under conditions similar to that of the production of the compound represented by the formula (Id) or a salt thereof by the reaction between the compound represented by the formula (Ic) or a salt thereof and the compound represented by the formula (IVb) or a salt thereof.
In the compounds represented by the formula (I) or salts thereof, a compound represented by the formula (It): 
wherein the symbols have the same meaning as described above, or a salt thereof is produced by allowing the compound represented by the formula (I) in which X is oxygen or a salt thereof to react with Lawesson""s reagent or phosphorus pentasulfide in a solvent selected from, for example, ether solvents (for example, diethylether, tetrahydrofuran and dioxane), hydrocarbon solvent (for example, benzene, toluene, hexane and heptane), alcohol solvents (for example, methanol, ethanol and propanol), haloid solvents (for example, dichlormethane and chloroform), hexamethylphosphoric triamide and dimethylsulfoxide. Lawesson""s reagent or phosphorus pentasulfide is used at this time in quantity of approximately 1 to 10 mol equivalent, preferably approximately 1 to 3 mol equivalent for 1 mol of the compound represented by the formula (I) in which X is oxygen or a salt thereof. The reaction temperature at this time is about 0 to 150xc2x0 C., preferably about 50 to 100xc2x0 C. The reaction time is about 1 to 24 hours, preferably about 3 to 10 hours.
The compound represented by the formula (Iu) can be produced by using the intermediate (IIIe) and the compound of the formula (IV) in substantially the same method of producing the compound Ia as described in the foregoing. 
The intermediate represented by the formula (IIIe) can be produced by the following method. Namely, the reaction for producing the compound represented by the formula (IIIe-1) or a salt thereof from the compound represented by the formula (IIIa-5) or a salt thereof can be conducted by allowing the starting compound to react with mercaptosuccinic acid in a hydrocarbon solvent (for example benzene, toluene and xylene) in the presence of an organic acid (for example methanesulfonic acid, p-toluenesulfonic acid and oxalic acid). The amount of the organic acid to be employed ranges, relative to 1 equivalent of the compound of the formula (IIIa-5), from 0.05 to 5 equivalents, preferably (0.05 to 0.1 equivalent). The reaction time ranges from 1 to 24 hours, preferably from 1 to 2 hours. The reaction temperature ranges from 20 to 140xc2x0 C., preferably from 80 to 100xc2x0 C. 
And, the reaction for producing the compound represented by the formula (IIIe) or a salt thereof from the compound represented by the formula (IIIe-1) or a salt thereof can be conducted in a hydrocarbon solvent (for example benzene, toluene and xylene). The reaction temperature ranges from 40 to 150xc2x0 C., preferably from 100 to 140xc2x0 C. The reaction time ranges from 1 to 24 hours, preferably from 12 to 20 hours.
And, the compound represented by the formula (Iv, Iw) can be produced by subjecting the compound represented by the formula (Iu) to oxidation. When this reaction is conducted by using m-chloro perbenzoic acid (1 to 1.2 equivalent), relative to 1 mol. of the compound represented by the formula (Iu), in a solvent such as an ether solvent (for example diethylether, tetrahydrofuran and dioxane) or a hydrocarbon solvent (for example dichloromethane, dichloroethane and chloroform) at xe2x80x9410 to 5xc2x0 C., preferably 0xc2x0 C. for 1 to 10 minutes, the compound represented by the formula (Iv) is obtained. While, in the case of conducting the reaction by using m-chloro perbenzoic acid (2 to 2.5 equivalents), relative to 1 mol. of the compound of the formula (Iu), at 10 to 50xc2x0 C., preferably 10 to 20xc2x0 C. for 2 to 5 hours, the compound represented by the formula (Iw) is produced. 
The starting compounds and intermediates of the present invention may be in form of salts but not specifically limited to them as the reaction proceeds. As salts of these compounds are used, for example, inorganic acid salts (for example, hydrochloride, sulfate, hydrobromide and phosphate), organic acid salts(for example, acetate, trifluoroacetate, succinate, maleate, fumarate, propionate, citrate, tartrate, malate, lactate, oxalate, methanesulfonate and p-toluene sulfonate), alkali metal salts (for example, sodium salt and potassium""salt), alkaline earth metal salts (for example, calcium salt and magnesium salt), organic base salts (for example, trimethylamine salt, triethylamine salt, pyridine salt, piperidine salt, ethanolamine salt), aluminum salt and ammonium salt. Further, the starting compounds and intermediates of the present invention may be used after isolation in usual manner. They may also be used without isolation for the subsquent reaction step.
When a compound has amino group, carboxy group and hydroxy group as the substituents in each of the above-mentioned reactions of the present invention, such protecting groups as those generally used in the peptide chemistry may be introduced to these groups. These protecting groups may be removed as occasion may demand to obtain an objective compound.
As the protecting group of the amino group are used, for example, formyl, C1-6 alkyl-carbonyl (for example, acetyl and ethylcarbonyl), benzyl, t-butyloxycarbonyl, benzyloxycarbonyl, 9-fluorenylmethyloxycarbonyl, allyoxycarbonyl, phenylcarbonyl, C1-6 alkyloxy-carbonyl (for example, methoxycarbonyl and ethoxy-carbonyl), C7-10 aralkyl-carbonyl (for example, benzylcarbonyl), trityl, phthaloyl and N,N-dimethylaminomethylene. These groups may be substituted by, for example, 1 to 3 halogen atoms (for example, fluorine, chlorine and bromine) and nitro.
As the protecting group-of the carboxy group are used, for example, C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl and t-butyl), phenyl, silyl and allyl. These groups may be substituted by, for example, 1 to 3 halogen atoms (for example, fluorine, chlorine and bromine) and nitro.
As the protecting group of the hydroxy group are used, for example, methoxymethyl, allyl, t-butyl, C7-10 aralkyl (for example, benzyl), formyl, C1-6 alkyl-carbonyl (for example, acetyl and ethylcarbonyl), benzolyl, furanyl and trialkylsilyl. These groups may be substituted by, for example, 1 to 3 halogen atoms (for example, fluorine, chlorine and bromine), C1-6 alkyl (for example, methyl, ethyl, propyl, isopropyl, butyl, t-butyl), phenyl, C7-10 aralkyl (for example, benzyl) and nitro.
As the method for removing these protecting groups is used a per se known method or a method corresponding thereoto, for example, a method employing acid, base, ultraviolet rays, hydrazine, phenylhydrazine, sodium N-methyldithiocarbamate, tetrabutylammonium fluoride and palladium acetate.
When a compound is obtained in the free form in each of the above-mentioned reactions of the present invention, the compound may be converted to a salt by a usual method and when obtained as a salt, it may be converted to the free form or to another salt.
A compound (I) of the present invention or a salt thereof thus obtained can be isolated and purified from the reaction solvent by known means, for example, phasic transfer, concentration, extraction by solvent, fractional distillation, crystallization, recrystallization and chromatography.
When a compound (I) of the present invention or a salt thereof is existing in the form of, for example, diastereomers and conformers, they may be isolated if required by a usual method for separation and purification. Further, when a compound (I) of the present invention or a salt thereof is a racemic compound, it may be separated into the d-compound and 1-compound by usual optical resolution means.
When a compound (I) of the present invention contains a basic group, it may be obtained as a medically acceptable acid addition""salt by a method corresponding to the per se known methods. As acids used for formation of such acid addition salts are mentioned, for example, inorganic acid (for example, hydrochloric acid, sulfuric acid, phosphoric acid and hydrobromic acid), organic acids (for example, acetic acid, trifluoroacetic acid, succinic acid, maleic acid, fumaric acid, propionic acid, citric acid, tartaric acid, malic acid, lactic acid, oxalic acid, methanesulfonic acid, p-toluenesulfonic acid) and amino acids (for example, glutamic acid and asparaginic acid). Further, when a compound (I) of the present invention contains an acid group, it may be made into a medically acceptable salt with a base by a method corresponding to the per se known methods. As bases used for formation of such salts with bases are mentioned, for example, alkali metals (for example, sodium and potassium), alkaline earth metals (for example, calcium and magnesium), organic bases (for example, trimethylamine, triethylamine, pyridine, piperidine and ethanolamine), aluminum and ammonium.
The compounds (I) of the present invention or salts thereof may be used in a wide variety of prophylactic, diagnostic, and therapeutic treatments of mammals(for example, human, cattle, horse, dog, cat, monkey, mouse and rat, especially, human) with low toxicity and with less adverse reactions. The compounds (I) of the present invention or salts thereof inhibit or modulate production or secretion of a variety of hormones, growth factors and physiologically active substances of mammals. As said xe2x80x9chormonesxe2x80x9d are mentioned, for example, growth hormones (GH), thyroid stimulating hormones (TSH), prolactin, insulin and glucagon. As said xe2x80x9cgrowth factorsxe2x80x9d are mentioned, for example, IGF-1. As said xe2x80x9cphysiologically active substancesxe2x80x9d are mentioned, for example, vasoactive intestinal polypeptide (VIP), gastcin, glucagon-like peptide-1, amylin, substance-P, CGRP, CCK(cholecystokinin) and amylase. And that said xe2x80x9cphysiologically active substancexe2x80x9d includes cytokines such as interleukins and TNF-xcex1. The compounds or salts thereof of this invention function through somatostatin receptors which couple to a variety of intracellular signal transduction systems. These systems include adenylyl cyclase, K+ channels, Ca2+ channels, protein phosphatases, phospholipaseC/IP3(inositol 1,4,5-trisphosphate), MAP kinase, a Na+/H+ exchanger, phospholipase A2, a transcription factor such as NF-xcexaB. The compounds or salts thereof of this invention modulate directly or indirectly cell proliferation inhibitory action of somatostatin and modulate apoptosis induced or regulated by somatostatin. The compounds or salts thereof of this invention may be used in a variety of diseases associated with disorders of production or secretion of hormones, growth factors, and physiologically active substances, associated with disorders of intracellular signal transduction systems, or associated with disorders of regulating cell proliferation. Preferably, the compounds or salts thereof of this invention may be useful (1) for drugs for treatment of for example, tumors such as acromegaly, TSH-producing tumors, nonsecretory (afunctional) hypophysial tumors, ectopic ACTH (adrenocorticotrophic hormone)-producing tumors, medullar thyroid carcinoma, VIP-producing tumors, glucagon-producing tumors, gastrin-producing tumors, insulinoma and cartinoid tumor, (2) for drugs for treatment of insulin-dependent and non-insulin dependent diabetes mellitus or a variety of diseases associated with them, for example, diabetic retinopathy, diabetic nephropathy, diabetic neuropathy, Doan syndrome and orthostatic hypotension, (3) for drugs for improvement of hyperinsulinemia or for treatment of obesity, for example, by inhibition of appetite (4) for drug for treatment of, for example, acute pancreatitis, chronic pancreatitis, pancreatointestinal fisutula, hemorrhagic ulcer, peptic ulcer, gastritis and hyperchylia by inhibition or modulation of the exocrine secretion in the digestive tracts, (5) for drugs for improvement of various symptoms associated with the Helicobacter pylori infection, for example, inhibitors of gastrin hypersecretion, (6) for drugs for inhibition of amylase secretion associated with endoscopic cholangiopancreatography, and drugs for prognostic treatment of surgical operation of pancreas, (7) for drugs for treatment of, for example, diarrhea due to intestinal malabsorption, promotion of secretion or dyskinesia of the digestive tracts(for example, short bowel syndrome), diarrhea due to the drugs for cancer chemotherapy, diarrhea due to AIDS, diarrhea due to graft versus host reaction (GVHR) associated with bone marrow transplantation, diarrhea due to diabetes mellitus, diarrhea due to celiac plexus blocking, diarrhea due to systemic sclerosis and diarrhea due to eosinophilia, (8) for drugs for treatment of, for example, dumping syndrome, irritable bowel syndrome, Crohn disease and inflammatory bowel disease, (9) for drugs for treatment of, for example, various cancers and tumors of which growth is dependent on insulin or IGF-1 or the other growth factors and various tumors and cancers associated with disorders of regulating cell proliferation caused by the other reasons (for example, thyroid cancer, colorectal cancer, breast cancer, prostatic cancer, small cell lung cancer, non-small cell cancer, pancreatic cancer, stomach cancer, cholangiocarcinoma, hepatic cancer, vesical cancer, ovarian cancer, melanoma, osteosarcoma, chondrosarcoma, malignant pheochromocytoma, neuro-blastoma, brain tumors, thymoma, renal cancers), leukemia (for example, leukemia of basophilic leukemia, chronic lymphocytic leukemia, chronic myeloid leukemia, Hodgkin disease, and non-Hodgkin lymphoma) (drugs for treatment of these cancers can be used for monotherapy or concomitant therapy with other anticancer drugs, for example, tamoxifen, LHRH agonists, LHRH antagonists, interferon-xcex1, Interferon-xcex2, interferon-xcex3 and interleukin-2), (10) for drugs for prevention and treatment of, for example, hypertrophic cardiomyopathy, arteriosclerosis, valvulopathy, myocardiac infarction (especially, myocardiac infarction post percutaneous transluminal coronary arterioplasty) and reangioplasty, (11) for drugs for treatment of hemorrhage of esophageal varicosis, cirrhosis and peripheral blood vessel disorders, (12) for drugs for treatment of, for example, diseases associated with general or local inflammation, for example, polyarteritis, rheumatoid arthritis, psoriasis, sunburn, eczema and allergy (for example, asthma, atopic dermatitis and allergic rhinitis) because they inhibit or modulate the secretion of physiologically active substances acting on the immune system (for example, Substance P, tachykinin and cytokines), (13) for drugs for treatment of, for example, dementia (for example, Alzheimer disease, Alzheimer-type senile dementia, vascular/multi-infarct dementia), headache, migraine, schizophrenia, epilepsy, depression, generalized anxiety disorder, sleep disorder, and multiple sclerosis, because they give influence on the production and secretion of nerve regulators, (14) for analgesic drugs, (15) for drugs for treatment of, for example, acute bacterial meningitis, acute virus encephalitis, adult respiratory distress syndrome (ARDS), bacterial pneumonia, severe systemic mycotic infection, tuberculosis, spinal damage, bone fracture, hepatic failure, pneumonia, alcoholic hepatitis, virus A hepatitis, virus B hepatitis, virus C hepatitis, AIDS infection, human papilloma virus infection, influenza infection, metastasis of cancer, multiple myeloma, osteomalacia, osteoporosis, bone Paget disease, reflux esophagitis, nephritis, renal failure, sepsis, septic shock, hypercalcemia, hypercholesterolemia, hypertriglyceridemia, hyperlipemia, systemic lupus erythematosus, transient ischemic attach and alcoholic hepatitis, (16) for cure of, for example, organ trasplant, burns, trauma, and alopecia, (17) ocular diseases for example glaucoma, (18) for imaging of tumors having somatostain receptor after introducing a radioactive substance (for example, 123I, 125I, 111In) to the compounds of the present invention either directly or via a proper spacer, and (19) targeting tumors with somatostatin receptors using the compounds in the present invention conjugated with anti-cancer drugs directly or using an appropriate spacer.
The compounds (I) of the present invention or salts thereof may be used as it is. They are usually formulated into pharmaceutical compositions together with pharmaceutical carriers by a usual method. As said xe2x80x9cpharmaceutical carriersxe2x80x9d are used, for example, excipients (for example, calcium carbonate, kaolin, sodium hydrogen carbonate, lactose, D-mannitol, starches, crystalline cellulose, talc, granulated sugar and porous substances), binders (for example, dextrin, gums, a-converted starch, gelatin, hydroxypropylcellulose, hydroxypropylmethylcellulose, prulan), agglutinants (for example, natural gums, cellulose derivatives and acrylic acid derivatives), disintegrants (for example, carboxymethylcellulose calcium, Croscarmellose sodium, Crospovidone, low-substituted hydroxypropylcelluloses and partially a-converted starch), solvents (for example, water for injection, alcohol, propyleneglycol, macrogol, sesame oil and corn oil), dispersants (for example, Tween 80, HCO 60, polyethyleneglycol, carboxymethylcellulose and sodium arginate), solubilizers (for example, polyethyleneglycol, propyleneglycol, D-mannitol, benzyl benzoate, ethanol, trisaminomethane, triethanolamine, sodium carbonate, sodium citrate), suspending agents (for example, stearyltriethanolamine, sodium laurylsulfate, benzalkonium chloride, polyvinyl alcohol and hydroxymethylcellulose), pain-killing agents (for example, benzyl alcohol), isotonicity agents (for example, sodium chloride and glycerin), buffers (for example, phosphates, acetates, carbonates and citrates), lubricants (for example, magnesium stearate, calcium stearate, talc, starch and sodium benzoate), colorants (for example, tar colors, caramel, red ferric oxide, titanium oxide, riboflavins). The medical preventive and curative drugs that may contain the above-described pharmaceutical carriers contain compounds (I) of the present invention or salts thereof in quantities required for prevention and treatment of a variety of diseases. The content of the compound (I) of the present invention or a medically acceptable salt thereof is usually about 0.1 to about 100 weight % of the whole pharmaceutical composition. As embodiments of the pharmaceutical compositions are used, for example, tablets (including sugar-coated tablets and film-coated tablets), pills, capsules (including microcapsules), granules, fine granules, powders, drip infusion preparations, syrups, emulsions, suspensions, injections, inhalants, ointments, suppositories, troches and poultices. These compositions are prepared according to a usual method (for example, the method described in the Japanese Pharmacopoeia 12th Edition).
The following are the methods for preparation of the main pharmaceutical compositions of the present invention, which naturally should not be construed as limiting thereto.
(1) Tablets
A compound of the present invention is mixed as it is or together with excipients, binders, disintegrating agents or other proper additives. The mixture is made into granules by a pertinent method. The granules are mixed with a lubricant and compressed into tablets. The tablets may be masked for taste or coated with a suitable coating material for the purpose of giving an enteric preparation or a sustained-release form.
(2) Injectables
A given amount of a compound of the present invention is dissolved, suspended or emulsified in, for example, water for injection, optionally adding to it a stabilizer, solubilizer, suspending agent, emulsifier, buffer and/or preservative to give a fixed dose.
(3) Suppository
An oily base, water-soluble base or other suitable base is optionally mixed with an emulsifier, suspending agent etc. A compound of the present invention is added to this, mixed and made into a proper form.
(4) Capsules
A compound of the present invention is mixed with an additive such as a proper excipient into a homogenous mixture or into granules by a proper method, or granules coated with a proper coating agent. The material thus obtained is softly filled in capsules as it is.
The pharmaceutical compositions of the present invention have a high safety with low toxicity and an excellent sbmatostatin agonistic action. They are therefore useful as drugs for prevention and treatment of the diseases mentioned above.
The quantities of the compounds of the present invention used in the above-mentiohed pharmaceutical compositions may vary with animal species to be administered and frequency of the administration. They show efficacy over a wide range of the dosage. For example, the daily oral dosage of a pharmaceutical composition of the present invention in adult acromegaly patients of acromegaly, diabetes, obesity, diabetic complication or inveterate diarrhea is usually approximately 0.001 to 20 mg/kg body weight, preferably approximately 0.2 to 3 mg/kg body weight as the effective dose of the compound (I) of the present invention. When the compounds are used in parenteral form, in combination with other active ingredients or concomitantly with other drugs, the dosage is generally lower than these dosages. The dosage of the compound actually administered is decided by the compound selected, dosage forms, the age, body weight, gender and severity of the disease of the patients, administration routes and the period and interval of the administration. So it is possible to change the dosage at any time at the discretion of physicians.
The administration routes of the above-described pharmaceutical compositions are not particularly limited to a variety of situations. They can be administered, for example, by the oral route or by the parenteral routes. The parenteral routes mentioned here include, for example, intravenous, intramuscular, subcutaneous, intranasal, intrarectal, intravaginal and intraperioneal routes.
The duration and interval of treatment with the above-described pharmaceutical compositions may be changed according to a variety of situations and may be decided at any time at the discretion of physicians. There are methods of, for example, administration in divided doses, administration for consecutive days, intermittent administration, massive administration for a short period and repeated administration. In case of oral administration, for example, it is desirable that they are administered either in one dose to several divided doses per day (1 to 3 times a day). It is also possible to administer the pharmaceutical composition intravenously by drip infusion over a longer time.
The present invention will be explained in more detail by the following examples and test examples. These are mere examples and are not intended to restrict the present invention, and may be modified within the range of not deviating from the scope of this invention.
In the examples and reference examples, abbreviations mean as follows.
s: singlet, d: doublet, t: triplet, q: quartet, dd: double doublet, m: multiplet, br broad, J: coupling constant, room temperature: 0-30xc2x0 C.